title: Discovery of 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamides as potent, selective dipeptidyl peptidase-4 (DPP4) inhibitors.
abstract: Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
authors.affiliation: Departments of Discovery Chemistry, Bristol-Myers Squibb, Research and Development, Princeton, New Jersey 08543-5400, USA. wei.meng@bms.com
authors.forename: Wei
authors.initials: W
authors.lastname: Meng
authors.forename: Robert P
authors.initials: RP
authors.lastname: Brigance
authors.forename: Hannguang J
authors.initials: HJ
authors.lastname: Chao
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrity
authors.forename: Jovita
authors.initials: J
authors.lastname: Marcinkeviciene
authors.forename: Stephen P
authors.initials: SP
authors.lastname: O'Connor
authors.forename: James K
authors.initials: JK
authors.lastname: Tamura
authors.forename: Dianlin
authors.initials: D
authors.lastname: Xie
authors.forename: Yaqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Klei
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Weigelt
authors.forename: Huji
authors.initials: H
authors.lastname: Turdi
authors.forename: Aiying
authors.initials: A
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kirby
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
mesh_terms: D000818:Animals; D020134:Catalytic Domain; 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; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C551946:6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo(1,2-a)pyrimidine-2-carboxamide; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007004:Hypoglycemic Agents; D007093:Imidazoles; C000606913:KCNH2 protein, human; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse