cis-2,5-Dicyanopyrrolidine Inhibitors of Dipeptidyl Peptidase IV:  Synthesis and in Vitro, in Vivo, and X-ray Crystallographic Characterization

• Published in: Journal of medicinal chemistry Vol. 49; no. 11; pp. 3068 - 3076
• Main Authors: Wright, Stephen W, Ammirati, Mark J, Andrews, Kim M, Brodeur, Anne M, Danley, Dennis E, Doran, Shawn D, Lillquist, Jay S, McClure, Lester D, McPherson, R. Kirk, Orena, Stephen J, Parker, Janice C, Polivkova, Jana, Qiu, Xiayang, Soeller, Walter C, Soglia, Carolyn B, Treadway, Judith L, VanVolkenburg, Maria A, Wang, Hong, Wilder, Donald C, Olson, Thanh V
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.06.2006; Amer Chemical Soc
• Subjects: Adenosine Deaminase - chemistry; Adenosine Deaminase Inhibitors; Administration, Oral; Animals; Biological and medical sciences; Biological Availability; Chemistry, Medicinal; Crystallography, X-Ray; Diabetes Mellitus, Type 2 - drug therapy; Dipeptidyl Peptidase 4 - chemistry; Dogs; General and cellular metabolism. Vitamins; Glycoproteins - antagonists & inhibitors; Glycoproteins - chemistry; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Injections, Intravenous; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Models, Molecular; Nitriles - chemical synthesis; Nitriles - chemistry; Nitriles - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; COMPLEX; POTENT; AMINES; CRYSTAL-STRUCTURE; STEREOCHEMISTRY; HOMOLOG; IV/CD26; DERIVATIVES; SUCCINALDEHYDE; Endocrinopathy; Type 2 diabetes; Nitrile; Intravenous administration; Nitrogen heterocycle; Modeling; Pyrrolidine derivatives; Hypoglycemic agent; Structure activity relation; Molecular model; Chemical synthesis; Monocyclic compound; Human; Enzyme; Aminoamide; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; Dipeptidyl dipeptidase; X ray diffraction; In vitro; Peptidases; In vivo; Chemotherapy; Experimental disease; Treatment; Animal; Hydrolases; Carboxamide; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0600085

Inhibitors of the glucagon-like peptide-1 (GLP-1) degrading enzyme dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes in animal models and in human subjects. A novel series of cis-2,5-dicyanopyrrolidine α-amino amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. 1-({[1-(Hydroxymethyl)cyclopentyl]amino}acetyl)pyrrolidine-2,5-cis-dicarbonitrile (1c) is an achiral, slow-binding (time-dependent) inhibitor of DPP-IV that is selective for DPP-IV over other DPP isozymes and proline specific serine proteases, and which has oral bioavailability in preclinical species and in vivo efficacy in animal models. The mode of binding of the cis-2,5-dicyanopyrrolidine moiety was determined by X-ray crystallography. The hydrochloride salt of 1c was further profiled for development as a potential new treatment for type 2 diabetes.