Open AccessPhosphorus-containing inhibitors of angiotensin-converting enzyme.
Author(s) -
Eugene D. Thorsett,
Elbert E. Harris,
Elwood R. Peterson,
William J. Greenlee,
Arthur A. Patchett,
Edgar H. Ulm,
Theodore C. Vassil
Publication year - 1982
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.79.7.2176
Subject(s) - dipeptide , chemistry , stereochemistry , enzyme , active site , angiotensin converting enzyme , hydrolase , carboxypeptidase , angiotensin ii , biochemistry , peptide , biology , endocrinology , receptor , blood pressure
Several phosphonamides, phosphoramides, and phosphates having the general structure R-Y-P(O)(OH)-X-CH(CH3)-CO-Pro have been synthesized and tested for inhibition of angiotensin-converting enzyme (dipeptidyl carboxypeptidase; peptidyl-dipeptide hydrolase, EC 3.4.15.1). Inhibition was found to depend on the nature of R, Y, and X such that the maximal effect was observed when X = NH, Y = CH2, and R = phi CH2 (50% inhibition at 7 nM). Substitution of CH2 or O at X and O at Y produced significantly less potent inhibitors. Groups shorter or longer than R = phi CH2 led to less active inhibitors, presumably due to nonoptimal interaction of the side chain with the S1 subsite.