Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors
| Autor: | Koichiro Mukoyoshi, Kaoru Yamagami, Kousei Yoshihara, Koji Yokoo, Susumu Yamaki, Fumie Takahashi, Toshihiro Hamajima, Yukihito Sugano, Koji Kato, Hidehiko Fukahori, Ayako Moritomo |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Class I Phosphatidylinositol 3-Kinases Pyridines Clinical Biochemistry Administration Oral Pharmaceutical Science Pharmacology Biochemistry Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Amide Drug Discovery Pyrazolopyridine Animals Humans Protein Kinase Inhibitors Molecular Biology Phosphoinositide-3 Kinase Inhibitors Biological evaluation Mice Inbred BALB C Molecular Structure Chemistry Organic Chemistry Nuclear Proteins Stereoisomerism Molecular Docking Simulation 030104 developmental biology Pyrazoles Molecular Medicine Female Selectivity Transcription Factors |
| Zdroj: | Bioorganic & Medicinal Chemistry. 26:2410-2419 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2018.03.042 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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