title: Optimization of activity, selectivity, and liability profiles in 5-oxopyrrolopyridine DPP4 inhibitors leading to clinical candidate (Sa)-2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778).
abstract: Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.
authors: Metabolic Diseases Chemistry, ‡Metabolic Diseases Biology, §Pharmaceutical Candidate Optimization, ∥Protein Science and Structure, ⊥Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-5400, United States.
authors: Pratik
authors: P
authors: Devasthale
authors: Ying
authors: Y
authors: Wang
authors: Wei
authors: W
authors: Wang
authors: John
authors: J
authors: Fevig
authors: JianXin
authors: J
authors: Feng
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: Frederic
authors: F
authors: Moulin
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: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: C584546:2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo(3,4-b)pyridin-6(7H)-yl)-N,N-dimethylacetamide; D000081:Acetamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011758:Pyrroles; D018819:Dipeptidyl Peptidase 4