ABSTRACT
A series of beta-aminoacylpiperidines bearing various fused five-membered heterocyclic rings was synthesized as dipeptidyl peptidase IV inhibitors. Potent and relatively selective inhibition could be obtained, depending on choice of heterocycle, regioisomerism, and substitution. In particular, one analog (74, DPP-IV IC50=26 nM) exhibited good oral bioavailability and acceptable half-life in the rat, albeit with rather high clearance.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Piperidines/chemical synthesis , Piperidines/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Isoxazoles , Oxazoles , Piperidines/chemistry , Protease Inhibitors/chemistry , Pyrazoles , ThiazolesABSTRACT
A diastereoselective synthesis was used to prepare a series of (3-substituted-cyclopentyl and -cyclohexyl)glycine pyrrolidides and thiazolidides. The three chiral centers were generated in an unambiguous, stereochemically defined manner. Inhibitory activity was dependent on the configuration at each stereocenter and on the nature of the 3-substituent. In the cyclopentylglycine pyrrolidide series, high potency against dipeptidyl peptidase IV and good selectivity could be achieved.
