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Optimization of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines to generate a highly selective PI3Kδ inhibitor. 2019
Toshihiro Hamajima, and
Fumie Takahashi, and
Koji Kato, and
Yukihito Sugano, and
Susumu Yamaki, and
Daisuke Suzuki, and
Ayako Moritomo, and
Satoshi Kubo, and
Koji Nakamura, and
Kaoru Yamagami, and
Koji Yokoo, and
Hidehiko Fukahori
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: toshihiro.hamajima@astellas.com.
Chemical optimization of the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (THPP) scaffold was conducted with a focus on cellular potency while maintaining high selectivity against PI3K isoforms. Compound 11f was identified as a potent, highly selective and orally available PI3Kδ inhibitor. In addition, 11f exhibited efficacy in an in vivo antibody production model. The desirable drug-like properties and in vivo efficacy of 11f suggest its potential as a drug candidate for the treatment of autoimmune diseases and leukocyte malignancies.
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