title: 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.
abstract: 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.
authors.affiliation: Departments of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 5400, Princeton, New Jersey 08543-5400, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Magnin
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sulsky
authors.forename: David J
authors.initials: DJ
authors.lastname: Augeri
authors.forename: Yanting
authors.initials: Y
authors.lastname: Huang
authors.forename: Ligaya M
authors.initials: LM
authors.lastname: Simpkins
authors.forename: Prakash C
authors.initials: PC
authors.lastname: Taunk
authors.forename: David A
authors.initials: DA
authors.lastname: Betebenner
authors.forename: James G
authors.initials: JG
authors.lastname: Robertson
authors.forename: Benoni E
authors.initials: BE
authors.lastname: Abboa-Offei
authors.forename: Aiying
authors.initials: A
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Cap
authors.forename: Li
authors.initials: L
authors.lastname: Xin
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.forename: Doree F
authors.initials: DF
authors.lastname: Sitkoff
authors.forename: Mary F
authors.initials: MF
authors.lastname: Malley
authors.forename: Jack Z
authors.initials: JZ
authors.lastname: Gougoutas
authors.forename: Ashish
authors.initials: A
authors.lastname: Khanna
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.forename: Song-Ping
authors.initials: SP
authors.lastname: Han
authors.forename: Rex A
authors.initials: RA
authors.lastname: Parker
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
mesh_terms: 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
chemical_list: D003521:Cyclopropanes; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D009570:Nitriles; D012996:Solutions; D011392:Proline; D018819:Dipeptidyl Peptidase 4