1981: Captopril and the ACE Inhibitor Class (1981)

Hypertension affected 15–20% of adults in industrialised countries by the 1970s but was poorly
treated: available antihypertensives (reserpine, hydralazine, methyldopa) were effective but
caused troublesome side effects. A rational biochemical approach to antihypertensive design
emerged from studies of angiotensin-converting enzyme (ACE), which catalyses the conversion of
the inactive peptide angiotensin I to the potent vasoconstrictor angiotensin II.

David Cushman and Miguel Ondetti at Squibb Pharmaceuticals applied a novel strategy: using the
known structure of ACE's active site—inferred from its similarity to carboxypeptidase A—to design
a competitive inhibitor. Teprotide, a snake venom peptide from Bothrops jararaca that inhibited
ACE, provided the biochemical proof of concept. Squibb chemists then designed small-molecule
mimetics of teprotide, reasoning that a compound bearing a sulfhydryl group to coordinate the
active site zinc would be a potent ACE inhibitor. This reasoning yielded captopril.

Captopril was approved by the FDA in April 1981 as the first orally active ACE inhibitor. Initial
use was for refractory hypertension, but clinical trials soon established efficacy in heart failure
(CONSENSUS trial, 1987), post-myocardial infarction (SAVE trial, 1992), and diabetic nephropathy
(Lewis trial, 1993). The drug demonstrably reduced mortality in each setting.

The captopril programme is considered the first example of structure-based drug design—designing
a drug molecule to fit a characterised enzyme active site—and validated this approach so
convincingly that it became the dominant paradigm for small-molecule drug discovery in the
following decades. The ACE inhibitor class, followed by angiotensin receptor blockers (ARBs),
became the most prescribed cardiovascular drug class worldwide.