The Discovery of Stendra™(Avanafil) for the Treatment of Erectile Dysfunction

Photochemical Skeletal Editing of Pyridines to Bicyclic Pyrazolines and Pyrazoles

“…However, this photochemical skeleton editing strategy has some limitations when applied to complex compounds. For instance, the carbon-deletion product pyrazole was not obtained for febuxostat (7), canagliflozin (9), and pyriproxyfen (10). Additionally, the bicyclic pyrazoline product was not accessible for drug molecules 12, 13, and 14.…”

“…Our study commenced with skeleton editing of nicotinyl alcohol (5) and nicotinamide derivative (6) (3-substituted pyridines), whereby three different new skeletons (including bicyclic pyrazolines 1ab, 1ab', 1aa, carbon [4,5] deletion pyrazole 2h, carbon [5,6] deletion pyrazole 4n, and 2-diazepines 3ag, 3af) could be readily constructed under mild conditions using this photochemical skeleton editing strategy. More complex drug derivatives such as the febuxostat derivative (7), ibuprofen derivative (8), and canagliflozin intermediate (9) were also well tolerated in this skeleton editing strategy, yielding the corresponding products in acceptable yields. The insect growth regulator pyriproxyfen (10) and stimulant laxative drug bisacodyl (11) with 2-substituted pyridine, as well as tropicamide derivative ( 12) with 4-substituted pyridine, were also susceptible to our method, affording the corresponding skeleton editing products in reasonable yields (such as bicyclic pyrazolines 1af, 1ag, carbon [2,3] deletion pyrazole 4p, carbon- [4,5] deletion pyrazole 2j, and 1,2-diazepines 3ak, 3al, and 3am).…”

“…5−9 For instance, Avanafil, which features a pyrimidine nucleus, has demonstrated superior relaxant effects on isolated rabbit corpus cavernosum compared to its analogues with pyridine, thiazole, or triazine nuclei (Figure 1A). 7 Other notable examples include the potent covalent inhibitor of KRASG12C (AMG 510) and its analogues, as well as COX-2 inhibitors etoricoxib and celecoxib (Figure 1B,C). 8,9 Pyridine, the second most common heterocycle found in FDA-approved drugs, plays a prevalent role in pharmaceuticals containing N-heterocycles.…”