Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors

Publication date: Available online 30 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Toshihiro Hamajima, Fumie Takahashi, Koji Kato, Koichiro Mukoyoshi, Kousei Yoshihara, Susumu Yamaki, Yukihito Sugano, Ayako Moritomo, Kaoru Yamagami, Koji Yokoo, Hidehiko Fukahori
phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure-activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice.

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