Researchers at the University were among the first to discover phosphodiesterase type 5 (PDE5) — the target of tadalafil — in the late 1970s and thereafter worked on the development of analogues of cGMP, a cyclic nucleotide that is hydrolysed by PDE5. Subsequently they then worked on the development of PDE5 inhibitors. In particular, they applied the results of their work on cGMP analogues to synthesize a new PDE5 inhibitor that was based on the structure of 3-isobutyl-1-methylxanthine (IBMX) — a non-selective PDE inhibitor commonly used as a research tool. By attaching a phenyl ring to position 8 and an electron-donating hydroxyl group at position 4 of the structure, a compound that was about 160-times more potent than IBMX at inhibiting PDE5 was generated, which was considered a potential treatment for erectile dysfunction.
This compound and other IBMX analogues were disclosed to GlaxoSmithKline (GSK) in February 1992 as part of a collaborative research proposal. In April of the same year, GSK assayed compounds for PDE5 activity, which led to the identification of a beta-carboline-based lead compound, and after further structural modifications became tadalafil. GSK assigned patent rights to its partner, ICOS Corporation, which is now part of Eli Lilly and Company.
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