Discovery, Optimization, and Evaluation of Quinazolinone Derivatives with Novel Linkers as Orally Efficacious Phosphoinositide-3-Kinase Delta Inhibitors for Treatment of Inflammatory Diseases

Kongjun Liu; Dan Li; Wei Zheng; Mingsong Shi; Yong Chen; Minghai Tang; Tao Yang; Min Zhao; Dexin Deng; Chufeng Zhang; Jiang Liu; Xue Yuan; Zhuang Yang; Lijuan Chen

doi:10.1021/acs.jmedchem.1c00004

Discovery, Optimization, and Evaluation of Quinazolinone Derivatives with Novel Linkers as Orally Efficacious Phosphoinositide-3-Kinase Delta Inhibitors for Treatment of Inflammatory Diseases

J Med Chem. 2021 Jul 8;64(13):8951-8970. doi: 10.1021/acs.jmedchem.1c00004. Epub 2021 Jun 17.

Authors

Kongjun Liu¹, Dan Li¹, Wei Zheng¹, Mingsong Shi¹, Yong Chen¹, Minghai Tang¹, Tao Yang¹, Min Zhao¹, Dexin Deng¹, Chufeng Zhang¹, Jiang Liu¹, Xue Yuan¹, Zhuang Yang^{1

2}, Lijuan Chen^{1

2}

Affiliations

¹ Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
² Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China.

PMID: 34138567
DOI: 10.1021/acs.jmedchem.1c00004

Abstract

Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade" of the propeller led to identification of a series of potent and selective PI3Kδ inhibitors. Among them, compound 50 afforded an optimum balance of PK profiles and potency. Oral administration of 50 attenuated the arthritis severity in a dose-dependent manner in a collagen-induced arthritis model without obvious toxicity. Furthermore, 50 demonstrated excellent pharmacokinetic properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Arthritis, Experimental / chemically induced
Arthritis, Experimental / drug therapy*
Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
Class I Phosphatidylinositol 3-Kinases / metabolism
Dose-Response Relationship, Drug
Drug Discovery
Humans
Inflammation / chemically induced
Inflammation / drug therapy*
Mice
Mice, Inbred DBA
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolinones / administration & dosage
Quinazolinones / chemistry
Quinazolinones / pharmacology*
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Protein Kinase Inhibitors
Quinazolinones
Class I Phosphatidylinositol 3-Kinases
PIK3CD protein, human