Synthesis of novel potent dipeptidyl peptidase IV inhibitors with enhanced chemical stability: interplay between the N-terminal amino acid alkyl side chain and the cyclopropyl group of alpha-aminoacyl-l-cis-4,5-methanoprolinenitrile-based inhibitors.
A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.
Magnin
David R
DR
Departments of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 5400, Princeton, New Jersey 08543-5400, USA.
Robl
Jeffrey A
JA
Sulsky
Richard B
RB
Augeri
David J
DJ
Huang
Yanting
Y
Simpkins
Ligaya M
LM
Taunk
Prakash C
PC
Betebenner
David A
DA
Robertson
James G
JG
Abboa-Offei
Benoni E
BE
Wang
Aiying
A
Cap
Michael
M
Xin
Li
L
Tao
Li
L
Sitkoff
Doree F
DF
Malley
Mary F
MF
Gougoutas
Jack Z
JZ
Khanna
Ashish
A
Huang
Qi
Q
Han
Song-Ping
SP
Parker
Rex A
RA
Hamann
Lawrence G
LG
D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D012996:Solutions
D003521:Cyclopropanes; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D009570:Nitriles; D012996:Solutions; D011392:Proline; D018819:Dipeptidyl Peptidase 4