title: 7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site.
abstract: Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 μM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 μmol/kg in ob/ob mice.
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA.
authors: Wei
authors: W
authors: Wang
authors: Pratik
authors: P
authors: Devasthale
authors: Aiying
authors: A
authors: Wang
authors: Tom
authors: T
authors: Harrity
authors: Don
authors: D
authors: Egan
authors: Nathan
authors: N
authors: Morgan
authors: Michael
authors: M
authors: Cap
authors: Aberra
authors: A
authors: Fura
authors: Herbert E
authors: HE
authors: Klei
authors: Kevin
authors: K
authors: Kish
authors: Carolyn
authors: C
authors: Weigelt
authors: Lucy
authors: L
authors: Sun
authors: Paul
authors: P
authors: Levesque
authors: Yi-Xin
authors: YX
authors: Li
authors: Robert
authors: R
authors: Zahler
authors: Mark S
authors: MS
authors: Kirby
authors: Lawrence G
authors: LG
authors: Hamann
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D007328:Insulin; D011725:Pyridines; D011758:Pyrroles; D051544:Cytochrome P-450 CYP3A; D018819:Dipeptidyl Peptidase 4