Ketopyrrolidines and ketoazetidines as potent dipeptidyl peptidase IV (DPP IV) inhibitors.
In this paper, the synthesis and structure-activity relationships (SAR) of two classes of electrophile-based dipeptidyl peptidase IV (DPP IV) inhibitors, the ketopyrrolidines and ketoazetidines, is discussed. The SAR of these series demonstrate that the 2-thiazole, 2-benzothiazole, and 2-pyridylketones are optimal S1' binding groups for potency against DPP IV. In addition, both cyclohexyl glycine (CHG) and octahydroindole carboxylate (OIC) serve as the most potent S2 binding groups within each series. Stereochemistry at the alpha-position of the central ring is relevant to potency within the ketopyrrolidines series, but not in the ketoazetidine series. Finally, the ketoazetidines display enhanced stability over the corresponding ketopyrrolidines, while maintaining their potency. In fact, certain stabilized ketoazetidines can maintain their in vitro potency and inhibit DPP IV in the plasma for up to 6h.
Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, MD 21224, USA.
Dana
D
Ferraris
Yao-Sen
YS
Ko
David
D
Calvin
Tiffany
T
Chiou
Susan
S
Lautar
Bert
B
Thomas
Krystyna
K
Wozniak
Camilo
C
Rojas
Vincent
V
Kalish
Sergei
S
Belyakov
D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D001384:Azetidines; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4