Synthesis and Src kinase inhibitory activity of 2-phenyl- and 2-thienyl-7-phenylaminothieno[3,2-b]pyridine-6-carbonitriles.
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.
Boschelli
Diane H
DH
Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. bosched@wyeth.com
Wu
Biqi
B
Barrios Sosa
Ana Carolina
AC
Durutlic
Haris
H
Chen
Joan J
JJ
Wang
Yan
Y
Golas
Jennifer M
JM
Lucas
Judy
J
Boschelli
Frank
F
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D009570:Nitriles; D011725:Pyridines; D013876:Thiophenes; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases