1. Pharma Research Center, Bayer AG, Aprather Wey 18a, D-42096 Wuppertal, Germany
2. Martin Luther University, School of Pharmacy, Wolfgang-Langenbeck-Strasse 4, D-06099 Halle, Germany
3. DLR, Institute of Aerospace Medicine, Linder Höhe, D-51147 Köln, Germany

Correspondence to: Johannes-Peter Stasch¹ Correspondence and requests for materials should be addressed to J.-P.S. (e-mail: Email: johannes-peter.stasch.js@bayer-ag.de).

Abstract

Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles¹. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (/) haem protein that converts GTP to cGMP^2–4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the ₁-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases.