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ID: ALA4715876
Journal: J Med Chem
Title: Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.
Authors: Shukla MR,Patra S,Verma M,Sadasivam G,Jana N,Mahangare SJ,Vidhate P,Lagad D,Tarage A,Cheemala M,Kulkarni C,Bhagwat S,Chaudhari VD,Sayyed M,Pachpute V,Phadtare R,Gole G,Phukan S,Sunkara B,Samant C,Shingare M,Naik A,Trivedi S,Marisetti AK,Reddy M,Gholve M,Mahajan N,Sabde S,Patil V,Modi D,Mehta M,Nigade P,Tamane K,Tota S,Goyal H,Volam H,Pawar S,Ahirrao P,Dinchhana L,Mallurwar S,Akarte A,Bokare A,Kanhere R,Reddy N,Koul S,Dandekar M,Singh M,Bernstein PR,Narasimham L,Bhonde M,Gundu J,Goel R,Kulkarni S,Sharma S,Kamboj RK,Palle VP
Abstract: PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.
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