Nitric oxide (NO) is a key mediator of neural and haemodynamic effects. NO diffuses into vascular smooth muscle cells, stimulating the production of cGMP and leading to vasodilatation.
The effects of NO/cGMP are limited by phosphodiesterase 5 (PDE5), which inactivates cGMP and is present in the smooth muscle of the vasculature and in platelets.
In 1986, novel pyrazolopyrimidines were identified as highly potent inhibitors of PDE5 at Pfizer laboratories as part of a programme seeking drugs for angina pectoris. A compound initially named UK-92,480, but now better known as sildenafil, was demonstrated to have very good potency and excellent selectivity over PDEs1–4.
During the 1980s, advances in the recognition and treatment of erectile dysfunction (ED), led to the use of drugs that function by modulating cAMP levels. However, drawbacks included the invasive nature of the treatment, induction of an 'artificial' erection and numerous side effects.
In the early 1990s sildenafil was looking less promising as an angina therapeutic. At the same time, experimental and clinical studies provided evidence that PDE5 inhibition might be an attractive therapeutic approach to ED, as NO is a key regulator of vascular tone in the corpus cavernosum.
By 1997, 21 separate clinical trials had demonstrated the efficacy of sildenafil in various patient populations. The FDA approved VIAGRA for the treatment of ED in March 1998. European approval followed in September 1998.
Pulmonary hypertension is a devastating disease of different origins of which the idiopathic form of pulmonary arterial hypertension (iPAH) is the best characterized. In the early 1990s, intravenous prostacyclin was introduced as the first specific treatment for iPAH; however, this therapy is hampered by various drawbacks.
Adaptation of perfusion distribution to well-ventilated areas of the lung is regulated by local NO/ cGMP signalling. PDE5 is abundantly expressed in lung tissue and is therefore an ideal target for the treatment of disorders in the pulmonary circulation.
Between 1998–2001, growing evidence demonstrated the efficacy of sildenafil in the treatment of pulmonary vascular disorders and led to the design of a large randomized, controlled, multinational trial, the SUPER-1 study. Sildenafil was approved by the FDA and the EMEA in 2005 for the treatment of PAH.
New potential indications currently under investigation include the treatment of pulmonary hypertension associated with underlying lung diseases (for example, chronic obstructive pulmonary disease and fibrosis), chronic thromboembolic pulmonary hypertension, Raynaud's phenomenon, right- and left-ventricular hypertrophy, and cerebrovascular diseases.
In less than 20 years, the first selective type 5 phosphodiesterase inhibitor, sildenafil, has evolved from a potential anti-angina drug to an on-demand oral treatment for erectile dysfunction (Viagra), and more recently to a new orally active treatment for pulmonary hypertension (Revatio). Here we describe the key milestones in the development of sildenafil for these diverse medical conditions, discuss the advances in science and clinical medicine that have accompanied this journey and consider possible future indications for this versatile drug.
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Marsh, N. & Marsh, A. A short history of nitroglycerine and nitric oxide in pharmacology and physiology. Clin. Exp. Pharmacol. Physiol. 27, 313–319 (2000).
Moncada, S., Palmer, R. M. & Higgs, E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43, 109–142 (1991). An excellent review of the physiology and pathophysiology of nitric oxide and the pharmacological implications of this important molecule.
Pfeifer, A. et al. Structure and function of cGMP-dependent protein kinases. Rev. Physiol. Biochem. Pharmacol. 135, 105–149 (1999).
Lucas, K. A. et al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol. Rev. 52, 375–414 (2000).
Parker, J. D. & Parker, J. O. Nitrate therapy for stable angina pectoris. N. Engl. J. Med. 338, 520–531 (1998).
Corbin, J. D. & Francis, S. H. Cyclic GMP phosphodiesterase-5: target of sildenafil. J. Biol. Chem. 274, 13729–13732 (1999). An informative review about sildenafil and its target, PDE5, from two scientists that contributed significantly to this research area.
Terrett, N. K., Bell, A. S., Brown, D. & Ellis, P. Sildenafil (VIAGRA(TM)), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg. Med. Chem. Lett. 6, 1819–1824 (1996).
Wallis, R. M., Corbin, J. D., Francis, S. H. & Ellis, P. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am. J. Cardiol. 83, 3C–12C (1999).
Campbell, S. F. Science, art and drug discovery: a personal perspective. Clin. Sci. (Lond) 99, 255–260 (2000).
Walker, D. K. et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 29, 297–310 (1999).
Ballard, S. A. et al. Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J. Urol. 159, 2164–2171 (1998).
Webb, D. J., Freestone, S., Allen, M. J. & Muirhead, G. J. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am. J. Cardiol. 83, 21C–28C (1999).
Ignarro, L. J. et al. Nitric oxide and cyclic GMP for-mation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem. Biophys. Res. Commun. 170, 843–850 (1990).
Bush, P. A., Aronson, W. J., Buga, G. M., Rajfer, J. & Ignarro, L. J. Nitric oxide is a potent relaxant of human and rabbit corpus cavernosum. J. Urol. 147, 1650–1655 (1992).
Azadzoi, K. M. et al. Endothelium-derived nitric oxide and cyclooxygenase products modulate corpus cavernosum smooth muscle tone. J. Urol. 147, 220–225 (1992).
Boolell, M. et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int. J. Impot. Res. 8, 47–52 (1996). First report from a Pfizer research group indicating that sildenafil holds promise as a new effective oral treatment for penile erectile dysfunction.
Rosen, R. C., Cappelleri, J. C. & Gendrano, N., III The International Index of Erectile Function (IIEF): a state-of-the-science review. Int. J. Impot. Res. 14, 226–244 (2002). Important review of the International Index of Erectile Function (IIEF), the current 'gold standard' measure for efficacy assessment in clinical trials of erectile dysfunction.
Eardley, I., Ellis, P., Boolell, M. & Wulff, M. Onset and duration of action of sildenafil for the treatment of erectile dysfunction. Br. J. Clin. Pharmacol. 53 (Suppl. 1), 61S–65S (2002).
Goldstein, I. et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N. Engl. J. Med. 338, 1397–1404 (1998). First publication of the results of two sequential double-blind studies proving the efficacy and safety of sildenafil, administered as needed in men with erectile dysfunction.
Montorsi, F. et al. Efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfunction of various etiologies. Urology 53, 1011–1018 (1999).
Dinsmore, W. W. et al. Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects. Urology 53, 800–805 (1999).
Stuckey, B. G. et al. Sildenafil citrate for treatment of erectile dysfunction in men with type 1 diabetes: results of a randomized controlled trial. Diabetes Care 26, 279–284 (2003).
Rendell, M. S., Rajfer, J., Wicker, P. A. & Smith, M. D. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. Sildenafil Diabetes Study Group. JAMA 281, 421–426 (1999).
Olsson, A. M. & Persson, C. A. Efficacy and safety of sildenafil citrate for the treatment of erectile dysfunction in men with cardiovascular disease. Int. J. Clin. Pract. 55, 171–176 (2001).
Fowler, C. J. et al. A double blind, randomised study of sildenafil citrate for erectile dysfunction in men with multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 76, 700–705 (2005).
Derry, F. A. et al. Efficacy and safety of oral sildenafil (Viagra) in men with erectile dysfunction caused by spinal cord injury. Neurology 51, 1629–1633 (1998).
Ogura, K. et al. Role of sildenafil citrate in treatment of erectile dysfunction after radical retropubic prostatectomy. Int. J. Urol. 11, 159–163 (2004).
Morales, A., Gingell, C., Collins, M., Wicker, P. A. & Osterloh, I. H. Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. Int. J. Impot. Res. 10, 69–73 (1998). Very informative data analysis on safety and tolerability of sildenafil in the treatment of erectile dysfunction from a series of double-blind, placebo-controlled studies and from ten open-label extension studies.
Gbekor, E., Bethell, S., Fawcett, L., Mount, N. & Phillips, S. Phosphodiesterase 5 inhibitor profiles against all human phosphodiesterase families: Implications for use as pharmacological tools. J. Urol. 167 (Suppl.), S246 (2002).
Laties, A. & Zrenner, E. Viagra (sildenafil citrate) and ophthalmology. Prog. Retin. Eye Res. 21, 485–506 (2002).
Marmor, M. F. & Kessler, R. Sildenafil (Viagra) and ophthalmology. Surv. Ophthalmol. 44, 153–162 (1999).
Abbott, D. et al. Preclinical safety profile of sildenafil. Int. J. Impot. Res. 16, 498–504 (2004).
Herrmann, H. C., Chang, G., Klugherz, B. D. & Mahoney, P. D. Hemodynamic effects of sildenafil in men with severe coronary artery disease. N. Engl. J. Med. 342, 1622–1626 (2000). First systematic clinical trial proving that sildenafil had no adverse cardiovascular effects in men with severe coronary artery disease.
Arruda-Olson, A. M., Mahoney, D. W., Nehra, A., Leckel, M. & Pellikka, P. A. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial. JAMA 287, 719–725 (2002).
DeBusk, R. F. et al. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am. J. Cardiol. 93, 147–153 (2004).
Wysowski, D. K., Farinas, E. & Swartz, L. Comparison of reported and expected deaths in sildenafil (Viagra) users. Am. J. Cardiol. 89, 1331–1334 (2002).
Boshier, A., Wilton, L. V. & Shakir, S. A. Evaluation of the safety of sildenafil for male erectile dysfunction: experience gained in general practice use in England in 1999. BJU Int. 93, 796–801 (2004).
Fox, K. M. et al. Sildenafil citrate does not reduce exercise tolerance in men with erectile dysfunction and chronic stable angina. Eur. Heart J. 24, 2206–2212 (2003).
Halcox, J. P. et al. The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J. Am. Coll. Cardiol. 40, 1232–1240 (2002).
Bocchi, E. A. et al. Sildenafil effects on exercise, neurohormonal activation, and erectile dysfunction in congestive heart failure: a double-blind, placebo-controlled, randomized study followed by a prospective treatment for erectile dysfunction. Circulation 106, 1097–1103 (2002).
Mahmud, A., Hennessy, M. & Feely, J. Effect of sildenafil on blood pressure and arterial wave reflection in treated hypertensive men. J. Hum. Hypertens. 15, 707–713 (2001).
Katz, S. D. et al. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J. Am. Coll. Cardiol. 36, 845–851 (2000).
Desouza, C., Parulkar, A., Lumpkin, D., Akers, D. & Fonseca, V. A. Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care 25, 1336–1339 (2002).
Ockaili, R., Salloum, F., Hawkins, J. & Kukreja, R. C. Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits. Am. J. Physiol. Heart Circ. Physiol. 283, H1263–H1269 (2002).
Zhang, R. et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33, 2675–2680 (2002).
Egan, R. & Pomeranz, H. Sildenafil (Viagra) associated anterior ischemic optic neuropathy. Arch. Ophthalmol. 118, 291–292 (2000).
Cunningham, A. V. & Smith, K. H. Anterior ischemic optic neuropathy associated with viagra. J. Neuroophthalmol. 21, 22–25 (2001).
Pomeranz, H. D., Smith, K. H., Hart, W. M. Jr. & Egan, R. A. Sildenafil-associated nonarteritic anterior ischemic optic neuropathy. Ophthalmology 109, 584–587 (2002).
Pomeranz, H. D. & Bhavsar, A. R. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases. J. Neuroophthalmol. 25, 9–13 (2005).
Gorkin, L., Hvidsten, K., Sobel, R. E. & Siegel, R. Sildenafil citrate use and the incidence of nonarteritic anterior ischemic optic neuropathy. Int. J. Clin. Pract. 60, 500–503 (2006).
Hattenhauer, M. G., Leavitt, J. A., Hodge, D. O., Grill, R. & Gray, D. T. Incidence of nonarteritic anterior ischemic optic neuropathy. Am. J. Ophthalmol. 123, 103–107 (1997).
Johnson, L. N. & Arnold, A. C. Incidence of nonarteritic and arteritic anterior ischemic optic neuropathy. Population-based study in the state of Missouri and Los Angeles County, California. J. Neuroophthalmol. 14, 38–44 (1994).
Fraunfelder, F. W., Pomeranz, H. D. & Egan, R. A. Nonarteritic anterior ischemic optic neuropathy and sildenafil. Arch. Ophthalmol. 124, 733–734 (2006).
Jackson, G., Gillies, H. & Osterloh, I. Past, present, and future: a 7-year update of Viagra (sildenafil citrate). Int. J. Clin. Pract. 59, 680–691 (2005).
Sanchez, L. S. et al. Cyclic-GMP-binding, cyclic-GMP-specific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development. Pediatr. Res. 43, 163–168 (1998).
Ziegler, J. W. et al. Effects of dipyridamole and inhaled nitric oxide in pediatric patients with pulmonary hypertension. Am. J. Respir. Crit. Care Med. 158, 1388–1395 (1998).
Ichinose, F., Adrie, C., Hurford, W. E., Bloch, K. D. & Zapol, W. M. Selective pulmonary vasodilation induced by aerosolized zaprinast. Anesthesiology 88, 410–416 (1998).
Ichinose, F., Adrie, C., Hurford, W. E. & Zapol, W. M. Prolonged pulmonary vasodilator action of inhaled nitric oxide by Zaprinast in awake lambs. J. Appl. Physiol. 78, 1288–1295 (1995).
Nagamine, J., Hill, L. L. & Pearl, R. G. Combined therapy with zaprinast and inhaled nitric oxide abolishes hypoxic pulmonary hypertension. Crit. Care Med. 28, 2420–2424 (2000).
Thusu, K. G., Morin, F. C., III, Russell, J. A. & Steinhorn, R. H. The cGMP phosphodiesterase inhibitor zaprinast enhances the effect of nitric oxide. Am. J. Respir. Crit. Care Med. 152, 1605–1610 (1995).
Humbert, M. et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 43, 13S–24S (2004).
Simonneau, G. et al. Clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 43, 5S–12S (2004).
Cogan, J. D. et al. Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genet. Med. 7, 169–174 (2005).
Lane, K. B. et al. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nature Genet. 26, 81–84 (2000).
Machado, R. D. et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am. J. Hum. Genet. 68, 92–102 (2001).
Galie, N., Manes, A. & Branzi, A. Emerging medical therapies for pulmonary arterial hypertension. Prog. Cardiovasc. Dis. 45, 213–224 (2002).
Barst, R. J. et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N. Engl. J. Med. 334, 296–302 (1996).
Badesch, D. B. et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann. Intern. Med. 132, 425–434 (2000).
Olschewski, H. et al. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann. Intern. Med. 124, 820–824 (1996).
Olschewski, H. et al. Inhaled iloprost to treat severe pulmonary hypertension. An uncontrolled trial. German PPH Study Group. Ann. Intern. Med. 132, 435–443 (2000).
Olschewski, H. et al. Inhaled iloprost for severe pulmonary hypertension. N. Engl. J. Med. 347, 322–329 (2002).
Olschewski, H. et al. Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension. Chest 124, 1294–1304 (2003).
Channick, R. et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: a placebo-controlled study. J. Heart Lung Transplant. 20, 262–263 (2001).
Rubin, L. J. et al. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med. 346, 896–903 (2002).
Bohle, R. M. et al. Cell type-specific mRNA quantitation in non-neoplastic tissues after laser-assisted cell picking. Pathobiology 68, 191–195 (2000).
German, Z. et al. Molecular basis of cell-specific endothelial nitric-oxide synthase expression in airway epithelium. J. Biol. Chem. 275, 8183–8189 (2000).
Ide, H. et al. Regulation of pulmonary circulation by alveolar oxygen tension via airway nitric oxide. J. Appl. Physiol. 87, 1629–1636 (1999).
Grimminger, F., Spriestersbach, R., Weissmann, N., Walmrath, D. & Seeger, W. Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs. J. Appl. Physiol. 78, 1509–1515 (1995). Interesting experimental work addressing the importance of lung nitric oxide production in the mediation of hypoxic pulmonary vasoconstriction.
Ghofrani, H. A. et al. Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension. J. Am. Coll. Cardiol. 43, 68S–72S (2004).
Weissmann, N. et al. Nitric oxide (NO)-dependent but not NO-independent guanylate cyclase activation attenuates hypoxic vasoconstriction in rabbit lungs. Am. J. Respir. Cell Mol. Biol. 23, 222–227 (2000).
Schulz, R. et al. Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy. Thorax 55, 1046–1051 (2000).
Spriestersbach, R., Grimminger, F., Weissmann, N., Walmrath, D. & Seeger, W. On-line measurement of nitric oxide generation in buffer-perfused rabbit lungs. J. Appl. Physiol. 78, 1502–1508 (1995).
Michelakis, E. D. The role of the NO axis and its therapeutic implications in pulmonary arterial hypertension. Heart Fail. Rev. 8, 5–21 (2003).
Ahn, H. S., Foster, M., Cable, M., Pitts, B. J. & Sybertz, E. J. Ca/CaM-stimulated and cGMP-specific phosphodiesterases in vascular and non-vascular tissues. Adv. Exp. Med. Biol. 308, 191–197 (1991).
Fink, T. L., Francis, S. H., Beasley, A., Grimes, K. A. & Corbin, J. D. Expression of an active, monomeric catalytic domain of the cGMP-binding cGMP-specific phosphodiesterase (PDE5). J. Biol. Chem. 274, 34613–34620 (1999).
Giordano, D., De Stefano, M. E., Citro, G., Modica, A. & Giorgi, M. Expression of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in mouse tissues and cell lines using an antibody against the enzyme amino-terminal domain. Biochim. Biophys. Acta 1539, 16–27 (2001).
Wharton, J. et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am. J. Respir. Crit. Care Med. 172, 105–113 (2005). Experimental study providing evidence for the antiproliferative effects of sildenafil in human pulmonary artery cells.
Corbin, J. D., Beasley, A., Blount, M. A. & Francis, S. H. High lung PDE5: A strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem. Biophys. Res. Commun. 334, 930–938 (2005). Notable work that explains on a cellular and molecular level the selectivity of PDE5 inhibitors for the pulmonary circulation.
Haynes, J., Jr., Kithas, P. A., Taylor, A. E. & Strada, S. J. Selective inhibition of cGMP-inhibitable cAMP phosphodiesterase decreases pulmonary vasoreactivity. Am. J. Physiol. 261, H487–H492 (1991).
Braner, D. A., Fineman, J. R., Chang, R. & Soifer, S. J. M&B 22948, a cGMP phosphodiesterase inhibitor, is a pulmonary vasodilator in lambs. Am. J. Physiol. 264, H252–H258 (1993).
Cohen, A. H. et al. Inhibition of cyclic 3′-5′-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats. J. Clin. Invest. 97, 172–179 (1996).
Zhao, L. et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 104, 424–428 (2001).
Zhao, L., Mason, N. A., Strange, J. W., Walker, H. & Wilkins, M. R. Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity. Circulation 107, 234–237 (2003).
Sebkhi, A., Strange, J. W., Phillips, S. C., Wharton, J. & Wilkins, M. R. Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. Circulation 107, 3230–3235 (2003).
Hanson, K. A. et al. Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity. Am. J. Physiol. 275, L931–L941 (1998).
Nangle, M. R., Cotter, M. A. & Cameron, N. E. An in vitro study of corpus cavernosum and aorta from mice lacking the inducible nitric oxide synthase gene. Nitric Oxide 9, 194–200 (2003).
Bloch, W. et al. Evidence for the involvement of endothelial nitric oxide synthase from smooth muscle cells in the erectile function of the human corpus cavernosum. Urol. Res. 26, 129–135 (1998).
Itoh, T. et al. A combination of oral sildenafil and beraprost ameliorates pulmonary hypertension in rats. Am. J. Respir. Crit. Care Med. 169, 34–38 (2004).
Schermuly, R. T. et al. Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am. J. Respir. Crit. Care Med. 169, 39–45 (2004).
Sitbon, O. et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension [see comments]. Eur. Respir. J. 12, 265–270 (1998).
Rossaint, R. et al. Inhaled nitric oxide for the adult respiratory distress syndrome. N. Engl. J. Med. 328, 399–405 (1993). Milestone work reporting the first therapeutic use of inhaled nitric oxide to treat acute pulmonary hypertension and gas-exchange disturbances in acute respiratory distress syndrome patients.
Atz, A. M. & Wessel, D. L. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 91, 307–310 (1999). First report of the use of sildenafil in human pulmonary hypertension to facilitate weaning from inhaled nitric oxide in paediatric patients.
Prasad, S., Wilkinson, J. & Gatzoulis, M. A. Sildenafil in primary pulmonary hypertension. N. Engl. J. Med. 343, 1342 (2000). First case report on the successful long-term therapy of one adult patient with severe idiopathic pulmonary arterial hypertension with oral sildenafil.
Abrams, D., Schulze-Neick, I. & Magee, A. G. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 84, E4 (2000).
Patole, S. & Travadi, J. Sildenafil for 'blue babies'. Ethics, conscience, and science have to be balanced against limited resources. BMJ 325, 1174 (2002).
Oliver, J. & Webb, D. J. Sildenafil for 'blue babies'. Such unlicensed drug use might be justified as last resort. BMJ 325, 1174 (2002).
Ghofrani, H. A. et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann. Intern. Med. 136, 515–522 (2002). First large clinical trial assessing the acute haemodynamic effects of sildenafil as compared with inhaled nitric oxide, inhaled iloprost or combinations of sildenafil and iloprost.
Wilkens, H. et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 104, 1218–1222 (2001).
Kothari, S. S. & Duggal, B. Chronic oral sildenafil therapy in severe pulmonary artery hypertension. Indian Heart J. 54, 404–409 (2002).
Sastry, B. K. et al. A study of clinical efficacy of sildenafil in patients with primary pulmonary hypertension. Indian Heart J. 54, 410–414 (2002).
Sastry, B. K., Narasimhan, C., Reddy, N. K. & Raju, B. S. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J. Am. Coll. Cardiol. 43, 1149–1153 (2004).
Ghofrani, H. A. et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J. Am. Coll. Cardiol. 42, 158–164 (2003). The first report of the successful long-term use of a combination therapy in patients with severe pulmonary hypertension.
Watanabe, H. et al. Sildenafil for primary and secondary pulmonary hypertension. Clin. Pharmacol. Ther. 71, 398–402 (2002).
Zimmermann, A. T., Calvert, A. F. & Veitch, E. M. Sildenafil improves right-ventricular parameters and quality of life in primary pulmonary hypertension. Intern. Med. J. 32, 424–426 (2002).
Singh, B. et al. Sildenafil in the management of primary pulmonary hypertension. Indian Heart J. 54, 297–300 (2002).
Lepore, J. J. et al. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am. J. Cardiol. 90, 677–680 (2002).
Michelakis, E. et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 105, 2398–2403 (2002).
Carlsen, J., Kjeldsen, K. & Gerstoft, J. Sildenafil as a successful treatment of otherwise fatal HIV-related pulmonary hypertension. AIDS 16, 1568–1569 (2002).
Schumacher, Y. O., Zdebik, A., Huonker, M. & Kreisel, W. Sildenafil in HIV-related pulmonary hypertension. AIDS 15, 1747–1748 (2001).
Ghofrani, H. A. et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am. J. Respir. Crit. Care Med. 167, 1139–1141 (2003).
Galie, N. et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med. 353, 2148–2157 (2005). Report on the pivotal randomized controlled trial which resulted in the final approval of oral sildenafil for the treatment of pulmonary arterial hypertension.
Moncada, I., Jara, J., Subira, D., Castano, I. & Hernandez, C. Efficacy of sildenafil citrate at 12 hours after dosing: re-exploring the therapeutic window. Eur. Urol. 46, 357–360 (2004).
Mullershausen, F. et al. Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling. J. Cell Biol. 160, 719–727 (2003).
Francis, S. H. et al. Ligand-induced conformational changes in cyclic nucleotide phosphodiesterases and cyclic nucleotide-dependent protein kinases. Methods 14, 81–92 (1998).
Gopal, V. K., Francis, S. H. & Corbin, J. D. Allosteric sites of phosphodiesterase-5 (PDE5). A potential role in negative feedback regulation of cGMP signaling in corpus cavernosum. Eur. J. Biochem. 268, 3304–3312 (2001).
Corbin, J. D. & Francis, S. H. Pharmacology of phosphodiesterase-5 inhibitors. Int. J. Clin. Pract. 56, 453–459 (2002).
Huai, Q., Liu, Y., Francis, S. H., Corbin, J. D. & Ke, H. Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity. J. Biol. Chem. 279, 13095–13101 (2004).
Michelakis, E. D. et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 108, 2066–2069 (2003).
CELORIA, G. C., FRIEDELL, G. H. & SOMMERS, S. C. Raynaud's disease and primary pulmonary hypertension. Circulation 22, 1055–1059 (1960).
SMITH, W. M. & KROOP, I. G. Raynaud's disease in primary pulmonary hypertension. JAMA 165, 1245–1248 (1957).
D'Alonzo, G. E. et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann. Intern. Med. 115, 343–349 (1991). Milestone report on the natural course of primary pulmonary hypertension based on data from the National Institutes of Health registry. Most currently published studies refer to this report if comparisons to a historic control are required.
Kallenberg, C. G. Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions. Curr. Opin. Rheumatol. 7, 568–573 (1995).
Pope, J. et al. Iloprost and cisaprost for Raynaud's phenomenon in progressive systemic sclerosis. Cochrane. Database. Syst. Rev. CD000953 (2000).
Belch, J. J. & Ho, M. Pharmacotherapy of Raynaud's phenomenon. Drugs 52, 682–695 (1996).
Boin, F. & Wigley, F. M. Understanding, assessing and treating Raynaud's phenomenon. Curr. Opin. Rheumatol. 17, 752–760 (2005).
Kamata, Y., Kamimura, T., Iwamoto, M. & Minota, S. Comparable effects of sildenafil citrate and alprostadil on severe Raynaud's phenomenon in a patient with systemic sclerosis. Clin. Exp. Dermatol. 30, 451 (2005).
Gore, J. & Silver, R. Oral sildenafil for the treatment of Raynaud's phenomenon and digital ulcers secondary to systemic sclerosis. Ann. Rheum. Dis. 64, 1387 (2005).
Rosenkranz, S. et al. Sildenafil improved pulmonary hypertension and peripheral blood flow in a patient with scleroderma-associated lung fibrosis and the raynaud phenomenon. Ann. Intern. Med. 139, 871–873 (2003).
Lichtenstein, J. R. Use of sildenafil citrate in Raynaud's phenomenon: comment on the article by Thompson et al. Arthritis Rheum. 48, 282–283 (2003).
Fries, R., Shariat, K., von, W. H. & Bohm, M. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. Circulation 112, 2980–2985 (2005). Original report of the first randomized controlled trial proving the efficacy of sildenafil to treat Raynauds's phenomenon.
Maurice, D. H. et al. Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Mol. Pharmacol. 64, 533–546 (2003).
Agusti, A. G. & Rodriguez-Roisin, R. Effect of pulmonary hypertension on gas exchange. Eur. Respir. J. 6, 1371–1377 (1993).
Ghofrani, H. A. et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 360, 895–900 (2002). The first clinical study to show that an oral vasodilator (sildenafil) can improve gas exchange, with comparable effects to those achievable with inhaled nitric oxide.
Ghofrani, H. A. et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. Ann. Intern. Med. 141, 169–177 (2004). This randomized controlled trial proved for the first time that effective treatment of hypoxic pulmonary hypertension with sildenafil results in improvements of exercise ability and right heart function under such conditions.
Richalet, J. P. et al. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am. J. Respir. Crit. Care Med. 171, 275–281 (2005).
Hsu, A. R. et al. Sildenafil improves cardiac output and exercise performance during acute hypoxia, but not normoxia. J. Appl. Physiol. (2006).
Naeije, R. Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 2, 20–22 (2005).
Higenbottam, T. Pulmonary hypertension and chronic obstructive pulmonary disease: a case for treatment. Proc. Am. Thorac. Soc. 2, 12–19 (2005).
Voelkel, N. F. & Cool, C. D. Pulmonary vascular involvement in chronic obstructive pulmonary disease. Eur. Respir. J. Suppl. 46, 28s–32s (2003).
Barbera, J. A., Peinado, V. I. & Santos, S. Pulmonary hypertension in chronic obstructive pulmonary disease. Eur. Respir. J. 21, 892–905 (2003).
Alp, S., Skrygan, M., Schmidt, W. E. & Bastian, A. Sildenafil improves hemodynamic parameters in COPD-an investigation of six patients. Pulm. Pharmacol. Ther. (2005).
Jessup, M. & Brozena, S. Heart failure. N. Engl. J. Med. 348, 2007–2018 (2003).
Anversa, P. et al. Ischemic cardiomyopathy: myocyte cell loss, myocyte cellular hypertrophy, and myocyte cellular hyperplasia. Ann. NY Acad. Sci. 752, 47–64 (1995).
Anversa, P., Capasso, J. M., Olivetti, G. & Sonnenblick, E. H. Cellular basis of ventricular remodeling in hypertensive cardiomyopathy. Am. J. Hypertens. 5, 758–770 (1992).
Kasimir, M. T. et al. Reverse cardiac remodelling in patients with primary pulmonary hypertension after isolated lung transplantation. Eur. J. Cardiothorac. Surg. 26, 776–781 (2004).
Wilkins, M. R. et al. Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) Study. Am. J. Respir. Crit. Care Med. 171, 1292–1297 (2005).
Kentera, D. & Susic, D. Dynamics of regression of right ventricular hypertrophy in rats with hypoxic pulmonary hypertension. Respiration 39, 272–275 (1980).
Rich, S. & Brundage, B. H. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation 76, 135–141 (1987).
Pelouch, V. et al. Regression of chronic hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and fibrosis: effect of enalapril. Cardiovasc. Drugs Ther. 11, 177–185 (1997).
O'Blenes, S. B., Fischer, S., McIntyre, B., Keshavjee, S. & Rabinovitch, M. Hemodynamic unloading leads to regression of pulmonary vascular disease in rats. J. Thorac. Cardiovasc. Surg. 121, 279–289 (2001).
Takimoto, E. et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nature Med. 11, 214–222 (2005). Milestone work highlighting the importance of PDE5 in the course of myocardial hypertrophy and the potential of the PDE5 inhibitor sildenafil as an antihypertrophic treatment.
Hassan, M. A. & Ketat, A. F. Sildenafil citrate increases myocardial cGMP content in rat heart, decreases its hypertrophic response to isoproterenol and decreases myocardial leak of creatine kinase and troponin T. BMC Pharmacol. 5, 10 (2005).
Katz, S. D. et al. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and chronic heart failure. Am. J. Cardiol. 95, 36–42 (2005).
Lepore, J. J. et al. Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide. Chest 127, 1647–1653 (2005).
Hirata, K., Adji, A., Vlachopoulos, C. & O'rourke, M. F. Effect of Sildenafil on Cardiac Performance in Patients With Heart Failure. Am. J. Cardiol. 96, 1436–1440 (2005).
Freitas, D., Athanazio, R., Almeida, D., Dantas, N. & Reis, F. Sildenafil improves quality of life in men with heart failure and erectile dysfunction. Int. J. Impot. Res. 18, 210–212 (2006).
Fisher, P. W., Salloum, F., Das, A., Hyder, H. & Kukreja, R. C. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation 111, 1601–1610 (2005).
Webster, L. J., Michelakis, E. D., Davis, T. & Archer, S. L. Use of sildenafil for safe improvement of erectile function and quality of life in men with New York Heart Association classes II and III congestive heart failure: a prospective, placebo-controlled, double-blind crossover trial. Arch. Intern. Med. 164, 514–520 (2004).
Alaeddini, J. et al. Efficacy and safety of sildenafil in the evaluation of pulmonary hypertension in severe heart failure. Am. J. Cardiol. 94, 1475–1477 (2004).
Guazzi, M., Tumminello, G., Di, M. F., Fiorentini, C. & Guazzi, M. D. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J. Am. Coll. Cardiol. 44, 2339–2348 (2004).
Mickley, H. & Poulsen, T. S. Use of sildenafil is safe in men with congestive heart failure. Arch. Intern. Med. 164, 2068 (2004).
Mikhail, N. Efficacy and safety of sildenafil in patients with congestive heart failure. Arch. Intern. Med. 164, 2067–2068 (2004).
Prickaerts, J. et al. Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat. Neuroscience 113, 351–361 (2002).
Blokland, A., Prickaerts, J., Honig, W. & de Vente, J. State-dependent impairment in object recognition after hippocampal NOS inhibition. Neuroreport 9, 4205–4208 (1998).
Kruuse, C., Thomsen, L. L., Jacobsen, T. B. & Olesen, J. The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects. J. Cereb. Blood Flow Metab. 22, 1124–1131 (2002).
Arnavaz, A. et al. Effect of sildenafil (Viagra) on cerebral blood flow velocity: a pilot study. Psychiatry Res. 122, 207–209 (2003).
Kruuse, C., Thomsen, L. L., Birk, S. & Olesen, J. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 126, 241–247 (2003).
Rosengarten, B., Huwendiek, O. & Kaps, M. Neurovascular coupling and cerebral autoregulation can be described in terms of a control system. Ultrasound Med. Biol. 27, 189–193 (2001).
Rosengarten, B., Osthaus, S. & Kaps, M. Doppler investigation of within-session reproducibility in a visual stimulation task to assess the volunteer-dependent variation. Cerebrovasc. Dis. 16, 53–60 (2003).
Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosci. 6, 43–50 (2003).
Sette, G. et al. Local brain haemodynamics and oxygen metabolism in cerebrovascular disease. Positron emission tomography. Brain 112 (Pt 4), 931–951 (1989).
Ito, H., Kanno, I., Takahashi, K., Ibaraki, M. & Miura, S. Regional distribution of human cerebral vascular mean transit time measured by positron emission tomography. Neuroimage 19, 1163–1169 (2003).
Kidwell, C. S., Villablanca, J. P. & Saver, J. L. Advances in neuroimaging of acute stroke. Curr. Atheroscler. Rep. 2, 126–135 (2000).
Lang, C. J. The use of neuroimaging techniques for clinical detection of neurotoxicity: a review. Neurotoxicology 21, 847–855 (2000).
Inoha, S. et al. Type V phosphodiesterase expression in cerebral arteries with vasospasm after subarachnoid hemorrhage in a canine model. Neurol. Res. 24, 607–612 (2002).
Zhang, R. et al. Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ. Res. 92, 308–313 (2003). Elegant work describing the importance of nitric oxide and cGMP in cerebral repair after stroke injury.
Buerk, D. G., Ances, B. M., Greenberg, J. H. & Detre, J. A. Temporal dynamics of brain tissue nitric oxide during functional forepaw stimulation in rats. Neuroimage 18, 1–9 (2003).
Rosengarten, B. et al. Sildenafil Improves Dynamic Vascular Function in the Brain: Studies in Patients with Pulmonary Hypertension. Cerebrovasc. Dis. 21, 194–200 (2005). First clinical study showing improvements in microvascular dynamic adaptation of blood flow to regional neuronal activity (demand-dependent perfusion) in the brain following sildenafil administration.
Wang, L., Gang, Z. Z., Lan, Z. R. & Chopp, M. Activation of the PI3-K/Akt pathway mediates cGMP enhanced-neurogenesis in the adult progenitor cells derived from the subventricular zone. J. Cereb. Blood Flow Metab. 25, 1150–1158 (2005).
Musicki, B. et al. Erection capability is potentiated by long-term sildenafil treatment: role of blood flow-induced endothelial nitric-oxide synthase phosphorylation. Mol. Pharmacol. 68, 226–232 (2005). Intriguing investigation suggesting a new mechanistic explanation for the long-term effects induced by sildenafil treatment, which differ from short-term vasodilatory effects of the same drug.
Francis, S. H., Turko, I. V. & Corbin, J. D. Cyclic nucleotide phosphodiesterases: relating structure and function. Prog. Nucleic Acid Res. Mol. Biol. 65, 1–52 (2001).
Fawcett, L. et al. Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc. Natl Acad. Sci. USA 97, 3702–3707 (2000).
Beavo, J. A. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. 75, 725–748 (1995). Excellent overview of PDEs and their functional implications by one of the most renowned scientists in this field.
Dousa, T. P. Cyclic-3′,5′-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Kidney Int. 55, 29–62 (1999).
Hayashi, M. et al. Molecular cloning and characterization of human PDE8B, a novel thyroid-specific isozyme of 3′,5′-cyclic nucleotide phosphodiesterase. Biochem. Biophys. Res. Commun. 250, 751–756 (1998).
Soderling, S. H., Bayuga, S. J. & Beavo, J. A. Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase. Proc. Natl Acad. Sci. USA 95, 8991–8996 (1998).
Yang, Q. et al. A novel cyclic GMP stimulated phosphodiesterase from rat brain. Biochem. Biophys. Res. Commun. 205, 1850–1858 (1994).
Pyne, N. J. & Furman, B. L. Cyclic nucleotide phosphodiesterases in pancreatic islets. Diabetologia 46, 1179–1189 (2003).
Glavas, N. A., Ostenson, C., Schaefer, J. B., Vasta, V. & Beavo, J. A. T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3. Proc. Natl Acad. Sci. USA 98, 6319–6324 (2001).
Brown, D. G. et al. Crystal structures of human phosphodiesterase 5 and its ligand complex and their use in the design of site-directed mutants and design or screening of inhibitor compounds. World Patent 2003038080 (2003).
Brown, D. G. et al. Crystal structures of human phosphodiesterase-5 and its ligand complex and their use in the design of site-directed mutants and design or screening of inhibitor compounds. World Patent 2004097010 (2004).
Our gratitude goes to R. Schermuly, N. Weissmann and R. Morty (from the University of Giessen Lung Center (UGLC)) and to G. Butrous, D. Brown and C. Wayman (from Pfizer Ltd., Sandwich) for thorough linguistic editing, helpful comments and input to the manuscript. This work was supported by the German research foundation (DFG; Sonderforschungsbereich 547).
H.A.G. has received honoraria for invited lectures from Schering AG, Altana Pharma, Pfizer, Actelion, CoTherix and United Therapeutics. H.A.G. is also a consultant to Altana Pharma, Schering AG, Pfizer, Novartis, Actelion and CoTehrix. H.A.G. has received unrestricted research grants from Altana Pharma and Pfizer. H.A.G. holds no stocks or shares of any of the aforementioned companies.
I.O. was responsible for the clinical development of Viagra for erectile dysfunction and is still a full-time employe of Pfizer Ltd (the manufacturer of Viagra). I.O. also holds shares in Pfizer.
F.G. has received honoraria for invited lectures from Schering AG, Altana Pharma and Pfizer. F.G. is also a consultant to Altana Pharma, Pfizer and Schering AG. F.G. has received unrestricted research grants from Altana Pharma, Bayer and Pfizer. F.G. holds no stocks or shres of any of the aforementioned companies.
- Angina pectoris
Severe chest pains caused by insufficient supply of blood to the heart.
Reduced responsiveness to a drug that is chronically supplied and requires dose up-titration to maintain the same level of efficacy over time.
- Corpus cavernosum
An expandable erectile tissue along the length of the penis, which fills with blood during male erection.
- Pulmonary hypertension
Increased blood pressure (>25 mm Hg at rest and >30 mm Hg for the mean pulmonary arterial pressure) in lung vessels.
- Alveolar hypoxia
Reduced oxygen levels (<80 mm Hg) in the lung alveoli caused by impaired ventilation (for example, in chronic lung disorders) or reduced oxygen content in the inspired air (for example, at high altitudes).
- Hypoxic pulmonary vasoconstriction
Constriction of pulmonary vessels in the presence of alveolar hypoxia, which prevents the perfusion of non-ventilated areas of lung and maintains optimized gas-exchange properties (also known as the von Euler–Liljestrand mechanism).
- Exercise tolerance
Ability to perform physical strain until limited by occurrence of peripheral (muscular) exhaustion, shortness of breath and/or insufficient blood supply to the myocardium (due, for example, to coronary heart disease).
- Neurovascular coupling
Mechanism by which local blood flow in the brain is adapted to underlying neuronal activity in a fast and fine-tuned manner.
About this article
Cite this article
Ghofrani, H., Osterloh, I. & Grimminger, F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 5, 689–702 (2006). https://doi.org/10.1038/nrd2030
British Journal of Pharmacology (2020)
Current Opinion in Pharmacology (2020)
Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing
Journal of Biomolecular Structure and Dynamics (2020)
Annual Review of Pharmacology and Toxicology (2020)
The exploration of novel Alzheimer’s therapeutic agents from the pool of FDA approved medicines using drug repositioning, enzyme inhibition and kinetic mechanism approaches
Biomedicine & Pharmacotherapy (2019)