title: Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.
abstract: Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
authors.affiliation: Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6001, USA. david.madar@abbott.com
authors.forename: David J
authors.initials: DJ
authors.lastname: Madar
authors.forename: Hana
authors.initials: H
authors.lastname: Kopecka
authors.forename: Daisy
authors.initials: D
authors.lastname: Pireh
authors.forename: Hong
authors.initials: H
authors.lastname: Yong
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wiedeman
authors.forename: Stevan W
authors.initials: SW
authors.lastname: Djuric
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Von Geldern
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fickes
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Bhagavatula
authors.forename: Todd
authors.initials: T
authors.lastname: McDermott
authors.forename: Steven
authors.initials: S
authors.lastname: Wittenberger
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Richards
authors.forename: Kenton L
authors.initials: KL
authors.lastname: Longenecker
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Lubben
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ballaron
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Long
authors.forename: Heidi
authors.initials: H
authors.lastname: Wells
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Zinker
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Mika
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Kempf-Grote
authors.forename: James
authors.initials: J
authors.lastname: Polakowski
authors.forename: Jason
authors.initials: J
authors.lastname: Segreti
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Reinhart
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: James M
authors.initials: JM
authors.lastname: Trevillyan
mesh_terms: D000243:Adenosine Deaminase / Q000737:chemistry; D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004285:Dogs; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / 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: C515139:2-(4-((2-(2-cyano-5-ethynyl-1-pyrrolidinyl)-2-oxoethyl)amino)-4-methyl-1-piperidinyl)-4-pyridinecarboxylic acid; D058892:Adenosine Deaminase Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D011725:Pyridines; D011759:Pyrrolidines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase