Diprolyl nitriles as potent dipeptidyl peptidase IV inhibitors.
Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM.
Zhao
Guohua
G
Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, NJ 08543-5400, USA. guohua.zhao@bms.com
Taunk
Prakash C
PC
Magnin
David R
DR
Simpkins
Ligaya M
LM
Robl
Jeffrey A
JA
Wang
Aiying
A
Robertson
James G
JG
Marcinkeviciene
Jovita
J
Sitkoff
Doree F
DF
Parker
Rex A
RA
Kirby
Mark S
MS
Hamann
Lawrence G
LG
D001665:Binding Sites; D003500:Cyclization; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary
D009570:Nitriles; D011480:Protease Inhibitors; D018819:Dipeptidyl Peptidase 4