Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation.

ID: ALA4368891

Journal: Medchemcomm

Title: Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation.

Authors: Ma X, Fang F, Tao Q, Shen L, Zhong G, Qiao T, Lv X, Li J.

Abstract: A series of structurally novel quinazolone-based PI3Kδ-selective inhibitors were designed and synthesized via the approach of conformational restriction. The majority of them exhibited two-digit to single-digit nanomolar IC₅₀ values against PI3Kδ, along with low micromolar to submicromolar GI₅₀ values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3Kδ inhibitory activity (IC₅₀ = 6.3 nM) and anti-proliferative activity (GI₅₀ = 0.21 μM) in this series, was further evaluated for its PI3Kδ selectivity, capability to down-regulate PI3K signaling in SU-DHL-6 cells, in vitro metabolic stability, and pharmacokinetic (PK) properties. The experimental results illustrated that this compound, as a promising lead, merits extensive structural optimization for exploring novel PI3Kδ-selective inhibitors as clinical candidates.

CiteXplore: 30996859

DOI: 10.1039/C8MD00556G

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