Design and synthesis of diversely substituted azacyclic inhibitors of endothelin converting enzyme.
A series of azacyclic phosphonic acids were synthesized from L-pyroglutamic acid, 6-oxo-L-pipecolic acid, and their enantiomers. The objective was to study the effect of constraining acyclic inhibitors of endothelin converting enzyme on inhibitory activity. Potential pharmacophoric tethers were introduced by stereocontrolled reactions to give highly substituted pyrrolidine- and piperidine-alpha-phosphonic acids. Weak inhibitory activity was observed for one diastereomer in each series having the same relative orientation of substituents.
Department of Chemistry, Université de Montréal, C. P. 6128, Succ. Centre-Ville, Montréal, P. Q., Canada H3C 3J7. stephen.hanessian@umontreal.ca
Stephen
S
Hanessian
Cécile
C
Gauchet
Guillaume
G
Charron
Julien
J
Marin
Philippe
P
Nakache
D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001372:Aza Compounds; D004791:Enzyme Inhibitors; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes