title: Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors.
abstract: A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
authors.affiliation: Department of Exploratory Pharmacokinetics and Pharmaceutics, Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA. zhonghua.pei@abbott.com
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.forename: Kenton
authors.initials: K
authors.lastname: Longenecker
authors.forename: Thomas W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wiedeman
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Lubben
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Zinker
authors.forename: Kent
authors.initials: K
authors.lastname: Stewart
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ballaron
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Mika
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Michelle
authors.initials: M
authors.lastname: Long
authors.forename: Heidi
authors.initials: H
authors.lastname: Wells
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Kempf-Grote
authors.forename: David J
authors.initials: DJ
authors.lastname: Madar
authors.forename: Todd S
authors.initials: TS
authors.lastname: McDermott
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Bhagavatula
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fickes
authors.forename: Daisy
authors.initials: D
authors.lastname: Pireh
authors.forename: Larry R
authors.initials: LR
authors.lastname: Solomon
authors.forename: Marc R
authors.initials: MR
authors.lastname: Lake
authors.forename: Rohinton
authors.initials: R
authors.lastname: Edalji
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Fry
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: James M
authors.initials: JM
authors.lastname: Trevillyan
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004355:Drug Stability; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D009570:Nitriles; D011480:Protease Inhibitors; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4