title: cis-2,5-dicyanopyrrolidine inhibitors of dipeptidyl peptidase IV: synthesis and in vitro, in vivo, and X-ray crystallographic characterization.
abstract: 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 alpha-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.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. stephen.w.wright@pfizer.com
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wright
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ammirati
authors.forename: Kim M
authors.initials: KM
authors.lastname: Andrews
authors.forename: Anne M
authors.initials: AM
authors.lastname: Brodeur
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Danley
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Doran
authors.forename: Jay S
authors.initials: JS
authors.lastname: Lillquist
authors.forename: Lester D
authors.initials: LD
authors.lastname: McClure
authors.forename: R Kirk
authors.initials: RK
authors.lastname: McPherson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Orena
authors.forename: Janice C
authors.initials: JC
authors.lastname: Parker
authors.forename: Jana
authors.initials: J
authors.lastname: Polivkova
authors.forename: Xiayang
authors.initials: X
authors.lastname: Qiu
authors.forename: Walter C
authors.initials: WC
authors.lastname: Soeller
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Soglia
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
authors.forename: Maria A
authors.initials: MA
authors.lastname: VanVolkenburg
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Donald C
authors.initials: DC
authors.lastname: Wilder
authors.forename: Thanh V
authors.initials: TV
authors.lastname: Olson
mesh_terms: D000243:Adenosine Deaminase / Q000737:chemistry*; D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D004285:Dogs; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C511630:1-(((1-(hydroxymethyl)cyclopentyl)amino)acetyl)pyrrolidine-2,5-dicarbonitrile; D058892:Adenosine Deaminase Inhibitors; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase