2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor.
2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Das
Jagabandhu
J
Bristol-Myers Squibb Pharmaceutical Research Institute, Post Office Box 4000, Princeton, New Jersey 08543-4000, USA. jagabandhu.das@bms.com
Chen
Ping
P
Norris
Derek
D
Padmanabha
Ramesh
R
Lin
James
J
Moquin
Robert V
RV
Shen
Zhongqi
Z
Cook
Lynda S
LS
Doweyko
Arthur M
AM
Pitt
Sidney
S
Pang
Suhong
S
Shen
Ding Ren
DR
Fang
Qiong
Q
de Fex
Henry F
HF
McIntyre
Kim W
KW
Shuster
David J
DJ
Gillooly
Kathleen M
KM
Behnia
Kamelia
K
Schieven
Gary L
GL
Wityak
John
J
Barrish
Joel C
JC
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D000069439:Dasatinib; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000097:blood / Q000139:chemically induced; D007376:Interleukin-2 / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007376:Interleukin-2; D008070:Lipopolysaccharides; D011743:Pyrimidines; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D000069439:Dasatinib