Design, synthesis, and biological evaluation of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives as orally bioavailable PI3K inhibitors

Daowei Huang; Jixia Yang; Qingwei Zhang; Xiaolei Zhou; Yanbo Wang; Zhenhua Shang; Jianqi Li; Baoyin Zhang

doi:10.3389/fphar.2024.1467028

Design, synthesis, and biological evaluation of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives as orally bioavailable PI3K inhibitors

Front Pharmacol. 2024 Oct 21:15:1467028. doi: 10.3389/fphar.2024.1467028. eCollection 2024.

Authors

Daowei Huang^#^{1

2

3}, Jixia Yang^#⁴, Qingwei Zhang⁵, Xiaolei Zhou⁶, Yanbo Wang⁷, Zhenhua Shang^{1

2

3}, Jianqi Li⁵, Baoyin Zhang⁸

Affiliations

¹ School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, China.
² Hebei Research Center of Pharmaceutical and Chemical Engineering, Shijiazhuang, China.
³ State Key Laboratory Breeding Base-Hebei Key Laboratory of Molecular Chemistry for Drug, Shijiazhuang, China.
⁴ School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, China.
⁵ Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, China.
⁶ School of Food Science and Biology, Hebei University of Science and Technology, Shijiazhuang, China.
⁷ Shijiazhuang Vortech Biotech Co., Ltd., Shijiazhuang, China.
⁸ Department of Pharmacy, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

^# Contributed equally.

Abstract

Introduction: Phosphoinositide-3-kinase (PI3K) is overexpressed in many tumors and is, thus, an ideal target for cancer treatments. Accordingly, there is an urgent need for the development of PI3K inhibitors with high potency and low toxicity.

Methods: In this study, we designed and synthesized a series of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives, which were evaluated for their PI3K inhibitory potency.

Results and discussion: Compound 17p demonstrated comparable PI3Kα inhibitory activity (IC₅₀: 31.8 ± 4.1 nM) to the positive control, BKM-120 (IC₅₀: 44.6 ± 3.6 nM). In addition, 17p showed significant inhibitory activity against PI3Kδ (IC₅₀: 15.4 ± 1.9 nM) and significant isoform selectivity against PI3Kβ, PI3Kγ, and mTOR. Furthermore, 17p exhibited good antiproliferative activities against cancer cell activity and good safety in the Ames and hERG tests while having outstanding liver microsomal stability in vitro, with half-lives of 38.5 min in rats and 127.9 min in humans. In addition, in an apoptosis assay, 17p could induce dose-dependent cytotoxicity in the ovarian cancer cell line A2780. In a pharmacokinetic study, 17p was stable (T _½: 2.03 h) and showed high bioavailability (46.2%). Collectively, these results indicate that 17p could be a promising PI3K agent for cancer treatment.

Keywords: 2; 4-dimorpholinopyrimidine-5-carbonitrile; PI3Ks; anti-cancer; bioavailability; synthesis.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was financially supported by the Medical Science and Technology Research Plan (Coordination) Project of Henan Province (No. LHGJ20190402), the Project of High-level Teachers Initiation Research of Hebei University of Chinese Medicine (No.1020103022), the Hebei Natural Science Foundation (H2024208001 and H2021208014), and the Medjaden Academy & Research Foundation for Young Scientists (Grant No. MJR20211124).