Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 24; pp. 6707 - 6713
• Main Authors: Corbett, J.W., Dirico, K., Song, W., Boscoe, B.P., Doran, S.D., Boyer, D., Qiu, X., Ammirati, M., VanVolkenburg, M.A., McPherson, R.K., Parker, J.C., Cox, E.D.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-12-2007; Elsevier
• Subjects: Amination; Animals; Benzene - chemistry; Biological and medical sciences; Cyanides - chemistry; Diabetes; Dipeptidyl Peptidase 4 - chemistry; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl peptidase IV; Dipeptidyl-Peptidase IV Inhibitors; Dogs; DPP-IV; Drug Design; General and cellular metabolism. Vitamins; Humans; Inhibitory Concentration 50; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Pyrroles - chemistry; Pyrroles - pharmacology; Rats; Stereoisomerism; Structure-Activity Relationship; Dipeptidyl peptidase IV; DPP-IV; Diabetes; Endocrinopathy; Nitrile; Rat; Pyrrolidine derivatives; Amine; Structure activity relation; Benzonitrile derivatives; Chemical synthesis; Dipeptidyl-peptidase IV; Stability; Enzyme; Diabetes mellitus; Rodentia; Oral administration; Enzyme inhibitor; In vitro; Peptidases; In vivo; Vertebrata; Mammalia; Animal; Hydrolases; Dofetilide; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.10.063

The
cis-3-amino-4-(2-cyanopyrrolidide)-pyrrolidine template has been shown to afford low nanomolar inhibitors of human DPP-IV that exhibit a robust PK/PD profile. An X-ray co-crystal structure of
5 confirmed the proposed mode of binding. The potent single digit DPP-IV inhibitor
53 exhibited a preferred PK/PD profile in preclinical animal models and was selected for additional profiling.