Ring-fused pyrazole derivatives as potent inhibitors of lymphocyte-specific kinase (Lck): Structure, synthesis, and SAR

Tetsuo Takayama; Hiroki Umemiya; Hideaki Amada; Tetsuya Yabuuchi; Takeshi Koami; Fumiyasu Shiozawa; Yusuke Oka; Akiko Takaoka; Akie Yamaguchi; Mayumi Endo; Masakazu Sato

doi:10.1016/j.bmcl.2009.11.013

Ring-fused pyrazole derivatives as potent inhibitors of lymphocyte-specific kinase (Lck): Structure, synthesis, and SAR

Bioorg Med Chem Lett. 2010 Jan 1;20(1):112-6. doi: 10.1016/j.bmcl.2009.11.013. Epub 2009 Nov 12.

Authors

Tetsuo Takayama¹, Hiroki Umemiya, Hideaki Amada, Tetsuya Yabuuchi, Takeshi Koami, Fumiyasu Shiozawa, Yusuke Oka, Akiko Takaoka, Akie Yamaguchi, Mayumi Endo, Masakazu Sato

Affiliation

¹ Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd, 403, Yoshino-Cho 1-Chome, Kita-Ku, Saitama-Shi, Saitama 331-9530, Japan. tetsuo.takayama@po.rd.taisho.co.jp

PMID: 19945867
DOI: 10.1016/j.bmcl.2009.11.013

Abstract

We have identified a novel series of ring-fused pyrazole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <1nM) as well as excellent cellular activity against mixed lymphocyte reaction (MLR) (IC(50)s <1nM).

MeSH terms

Adenosine Triphosphate / chemistry
Binding Sites
Computer Simulation
Crystallography, X-Ray
Hydrogen Bonding
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
Lymphocytes / drug effects
Lymphocytes / metabolism
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Pyrroles / chemical synthesis
Pyrroles / chemistry*
Pyrroles / pharmacology
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrroles
Adenosine Triphosphate
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)