Diastereoselective synthesis and configuration-dependent activity of (3-substituted-cycloalkyl)glycine pyrrolidides and thiazolidides as dipeptidyl peptidase IV inhibitors.
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.
Ashton
Wallace T
WT
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. wally_ashton@merck.com
Dong
Hong
H
Sisco
Rosemary M
RM
Doss
George A
GA
Leiting
Barbara
B
Patel
Reshma A
RA
Wu
Joseph K
JK
Marsilio
Frank
F
Thornberry
Nancy A
NA
Weber
Ann E
AE
D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects* / Q000378:metabolism*; D008968:Molecular Conformation; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D011480:Protease Inhibitors; D011759:Pyrrolidines; D013844:Thiazoles; D018819:Dipeptidyl Peptidase 4