Optimization of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines to generate a highly selective PI3Kδ inhibitor

[Display omitted] 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 inhib...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2019-03, Vol.27 (6), p.1056-1064
Main Authors: Hamajima, Toshihiro, Takahashi, Fumie, Kato, Koji, Sugano, Yukihito, Yamaki, Susumu, Suzuki, Daisuke, Moritomo, Ayako, Kubo, Satoshi, Nakamura, Koji, Yamagami, Kaoru, Yokoo, Koji, Fukahori, Hidehiko
Format: Article
Language:English
Subjects:
5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidine
Animals
Cells, Cultured
Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Class I Phosphatidylinositol 3-Kinases - metabolism
Female
Humans
Isoform selectivity
Mice, Inbred BALB C
Molecular Docking Simulation
Phosphoinositide-3 Kinase Inhibitors - chemistry
Phosphoinositide-3 Kinase Inhibitors - pharmacokinetics
Phosphoinositide-3 Kinase Inhibitors - pharmacology
PI3Kδ inhibitor
Pyrrolidines - chemistry
Pyrrolidines - pharmacokinetics
Pyrrolidines - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2019.02.001