Small-molecule inhibitor: candoxatril

Name

History: The design and synthesis of candoxatril and related compounds were described by Danilewicz et al. (1989) (Pfizer).
Peptidases inhibited: Known primarily as an inhibitor of neprilysin, but also inhibits endothelin-converting enzyme-1. It is a more potent inhibitor of neprilysin (K_i 14 nM: Danilewicz et al., 1989) than is thiorphan.
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: Neprilysin makes a major contribution to the destruction of atrial natriuretic factor (ANF) in vivo, and since ANF has a blood-pressure-lowering activity an inhibitor of its destruction has potential therapeutic value (Danilewicz et al. (1989)).
DrugBank: DB00616

CID at PubChem: 166585
ChEBI: 380571
Structure
Chemical/biochemical name: 4-[1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentyl]carbonylaminocyclohexane-1-carboxylic acid
Formula weight: 399
Related inhibitors: Candoxatril (UK-79,300) is the orally active prodrug of candoxatrilat (UK-73,967), the active enantiomer of (+/-) candoxatrilat (UK-69,578) (McDowell & Nicholls, 2000).

Inhibitor class: This is a compound in the carboxylate class of reversible metallopeptidase inhibitors. In these, the active site zinc of the enzyme is generally coordinated by a carboxylate of the inhibitor, and this interaction contributes to inhibitory potency. Reviewed by Patchett & Cordes (1985) and Powers & Harper (1986), pp. 268 - 277 (who provide a table of K_i values).