title: Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
abstract: Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.
authors.affiliation: Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, 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: Thomas W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: David J
authors.initials: DJ
authors.lastname: Madar
authors.forename: Kenton
authors.initials: K
authors.lastname: Longenecker
authors.forename: Hong
authors.initials: H
authors.lastname: Yong
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Lubben
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Zinker
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Backes
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Judd
authors.forename: Mathew
authors.initials: M
authors.lastname: Mulhern
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: Glenn A
authors.initials: GA
authors.lastname: Reinhart
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Lee C
authors.initials: LC
authors.lastname: Preusser
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Kempf-Grote
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: James M
authors.initials: JM
authors.lastname: Trevillyan
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D053138:Cyclohexenes / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats; D011924:Rats, Zucker; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014961:X-Ray Diffraction
chemical_list: C515232:ABT 341; D001713:Biphenyl Compounds; D053138:Cyclohexenes; D007004:Hypoglycemic Agents; D015842:Serine Proteinase Inhibitors; D014230:Triazoles; C052568:cyclohexene; D018819:Dipeptidyl Peptidase 4