Modern Drug Discovery
November/December 1998
Modern Dr ug Discovery, 1998, 1 (2), 31, 33-34, 36, 38.
Copyright &# 169; 1998 by the American Chemical Society.

Viagra diagram

Viagra was discovered using a rational drug design approach

Terrett et al. launched their search for a PDE 5 inhibitor with the choice of Zaprinast as their chemical starting point (1). Zaprinast was one of the very few cGMP PDE inhibitors known in 1986, albeit one that was weak and nonselective. Originially developed as an antiallergy compound, it is a vasodilator in vitro and lowers blood pressure in anesthetized dogs.

Noting that the heterocycles on Zaprinast and cGMP had similar sizes and shapes, the team explored a large variety of ring-system substitutes for the Zaprinast heterocycle. They tested their new compounds for improved affinity and selectivity by using in vitro PDE enzyme-inhibition assays. Later, they had to make substitutions elsewhere in the improved inhibitor to maximize solubility and reduce lipophilicity. The end result, UK-92,480, or Viagra (sildenafil citrate), selectively inhibited PDE 5. In a canine coronary artery assay, Viagra elevated cGMP and left cAMP levels unchanged, which would be expected of a PDE 5 inhibitor. Pharmacokinetic data for Viagra in humans and dogs were very similar.

IC50 values for PDE inhibition assaysa

PDE 1 PDE 3 PDE 5
Zaprinast 9.4 µM 58 µM 2.0 µM
UK-92,480 260 nM 65 µM 3.6 nM
aEnzymes of animal origin

Reference
(1) Terrett, N. K. et al, Sildenafil (Viagra), a potent and selective inhibitor of Type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824.


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