Synthesis and Src kinase inhibitory activity of 2-phenyl- and 2-thienyl-7-phenylaminothieno[3,2-b]pyridine-6-carbonitriles

Diane H Boschelli; Biqi Wu; Ana Carolina Barrios Sosa; Haris Durutlic; Joan J Chen; Yan Wang; Jennifer M Golas; Judy Lucas; Frank Boschelli

doi:10.1021/jm050175p

Synthesis and Src kinase inhibitory activity of 2-phenyl- and 2-thienyl-7-phenylaminothieno[3,2-b]pyridine-6-carbonitriles

J Med Chem. 2005 Jun 2;48(11):3891-902. doi: 10.1021/jm050175p.

Authors

Diane H Boschelli¹, Biqi Wu, Ana Carolina Barrios Sosa, Haris Durutlic, Joan J Chen, Yan Wang, Jennifer M Golas, Judy Lucas, Frank Boschelli

Affiliation

¹ Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. bosched@wyeth.com

PMID: 15916442
DOI: 10.1021/jm050175p

Abstract

2-phenyl-7-phenylaminothieno[3,2-b]pyridine-6-carbonitriles were recently reported to be inhibitors of Src kinase activity. In this study we present structure-activity relationships for additional thieno[3,2-b]pyridine-6-carbonitriles, modifying the substituents on the C-2 phenyl and C-7 phenylamino groups. Derivatives with various aminomethyl and aminoethyl substituents on the para position of the C-2 phenyl group retained the activity of the initial analogues. However, direct attachment of an amino group led to decreased activity. A 2,4-dichloro-5-methoxyphenylamino group at C-7 provided superior inhibition of Src enzymatic activity. Replacement of the C-2 phenyl group with a 3,5-substituted thiophene led to improved Src inhibitory activity compared to the parent compound, but other thiophene isomers were less active. One of the analogues reported here exhibited in vivo activity comparable to that of SKI-606, a related 3-quinolinecarbonitrile currently in clinical trials.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Biological Availability
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Female
Fibroblasts / cytology
Fibroblasts / drug effects
Fibroblasts / enzymology
Humans
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
Mice
Mice, Nude
Nitriles / chemical synthesis*
Nitriles / chemistry
Nitriles / pharmacology
Proto-Oncogene Proteins c-abl / antagonists & inhibitors
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology
Rats
Structure-Activity Relationship
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology
Transfection
Xenograft Model Antitumor Assays
src-Family Kinases / antagonists & inhibitors*
src-Family Kinases / genetics

Substances

Antineoplastic Agents
Nitriles
Pyridines
Thiophenes
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Proto-Oncogene Proteins c-abl
src-Family Kinases