title: Hydroxamic acids as potent inhibitors of endothelin-converting enzyme from human bronchiolar smooth muscle.
abstract: Hydroxamic acids 6a-h, derived from malonyl amino acids, and 25a-d, derived from succinyl amino acids, were synthesized as inhibitors of human bronchiolar smooth muscle endothelin-converting enzyme (HBSM ECE). Several unexpected side reactions were discovered, particularly in the synthesis of hydroxamates derived from succinates. In vitro evaluation against human bronchiolar ECE revealed that in all cases hydroxamates derived from malonate were more potent than hydroxamates derived from succinate. Isopropyl and isobutyl P1' side chains were suitable; omission of the P1' side chain seriously diminished potency. In the P2' position, several amino acids gave potent malonate-derived hydroxamate inhibitors (6b, d-h, IC50 = 0.2-6.8 nM), and beta-Ala provided an extremely potent inhibitor (6c, IC50 = 0.01 nM). C-terminus carboxylates are much more potent ECE inhibitors than the corresponding amides. Most of the hydroxamates were also potent inhibitors of thermolysin and neutral endopeptidase (NEP); however, the P2' beta-Ala derivative 6c uniquely inhibited HBSM ECE much more potently than NEP.
authors.affiliation: Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bihovsky
authors.forename: B L
authors.initials: BL
authors.lastname: Levinson
authors.forename: R C
authors.initials: RC
authors.lastname: Loewi
authors.forename: P W
authors.initials: PW
authors.lastname: Erhardt
authors.forename: M A
authors.initials: MA
authors.lastname: Polokoff
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001980:Bronchi / Q000166:cytology / Q000201:enzymology*; D002478:Cells, Cultured; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology*
chemical_list: D006877:Hydroxamic Acids; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes