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)

Pratik Devasthale; Ying Wang; Wei Wang; John Fevig; JianXin Feng; Aiying Wang; Tom Harrity; Don Egan; Nathan Morgan; Michael Cap; Aberra Fura; Herbert E Klei; Kevin Kish; Carolyn Weigelt; Lucy Sun; Paul Levesque; Frederic Moulin; Yi-Xin Li; Robert Zahler; Mark S Kirby; Lawrence G Hamann

doi:10.1021/jm4008906

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)

J Med Chem. 2013 Sep 26;56(18):7343-57. doi: 10.1021/jm4008906. Epub 2013 Sep 9.

Affiliation

¹ 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.

PMID: 23964740
DOI: 10.1021/jm4008906

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.

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry*
Acetamides / pharmacology*
Animals
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic / chemistry*
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Catalytic Domain
Dipeptidyl Peptidase 4 / chemistry
Dipeptidyl Peptidase 4 / metabolism*
Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
Dipeptidyl-Peptidase IV Inhibitors / chemistry*
Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
Drug Design*
Glucose Tolerance Test
Humans
Male
Mice
Models, Molecular
Pyrroles / chemical synthesis
Pyrroles / chemistry*
Pyrroles / pharmacology*
Substrate Specificity

Substances

2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo(3,4-b)pyridin-6(7H)-yl)-N,N-dimethylacetamide
Acetamides
Bridged Bicyclo Compounds, Heterocyclic
Dipeptidyl-Peptidase IV Inhibitors
Pyrroles
Dipeptidyl Peptidase 4