Small-molecule inhibitor: CGS 35601

Summary Literature


Common name
CGS 35601
Other names
CGS 37808 (prodrug)


CGS 35601 and its orally-active prodrug CGS 37808 were described by Trapani et al. (2004).
Peptidases inhibited
CGS 35601 inhibits angiotensin-converting enzyme compound peptidase (ACE), neprilysin and endothelin converting enzyme (ECE) simultaneously, with IC50 values of 22, 2, and 55 nM, respectively (Battistini et al., 2005).
The reversible inhibition is attributable to interactions including that of the thiol group of the inhibitor with the essential zinc atoms of the metalloenzymes.
Pharmaceutical relevance
Through the inhibition of ACE and ECE, CGS 35601 blocks the conversion of angiotensin I and big endothelin-1 into the two most potent vasoconstrictor peptides, angiotensin II and endothelin-1, respectively. By inhibiting neprilysin, CGS 35601 also prevents the degradation of vasodilator peptides such as bradykinin, natriuretic peptides and adrenomedullin and thus modulates the secondary release of other vasoactive mediators such as nitric oxide and prostaglandins (Battistini et al., 2005).


Chemical/biochemical name
L-tryptophan, N-[[1-[[(2S)-2->mercapto-4-methyl-1-oxopentyl]amino]-cyclopentyl]carbonyl]
Related inhibitors
A prodrug is CGS 37808 (L-tryptophan, N-[[1-[[(2S)-2-(acetylthio)-4-methyl-1-oxopentyl]amino]cyclopentyl]-carbonyl]-, methyl ester)


Inhibitor class
This compound is a thiol-containing metallopeptidase inhibitor. In these, an interaction between the thiol group of the inhibitor and zinc in the active site of the enzyme contributes to inhibitory potency. Among the first of such compounds to be described was captopril (Cushman et al., 1977). Reviewed by Powers & Harper (1986), pp. 254 - 263. Thiol-containing metallopeptidase inhibitors include captopril, CGS 35601, GEMSA, omapatrilat, RB 101(S), thiorphan.
For obvious reasons, inhibitors of this type are often termed 'triple vasopeptidase inhibitors'.