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

被引：12

作者：

Shukla, Manojkumar R. ^{[1
]}

Patra, Sukanya ^{[1
]}

Verma, Mahip ^{[1
]}

Sadasivam, Gayathri ^{[1
]}

Jana, Nirmal ^{[1
]}

Mahangare, Sachin J. ^{[1
]}

Vidhate, Prashant ^{[1
]}

Lagad, Dipak ^{[1
]}

Tarage, Anand ^{[1
]}

Cheemala, Murthy ^{[1
]}

Kulkarni, Chaitanya ^{[1
]}

Bhagwat, Shankar ^{[1
]}

Chaudhari, Vinod D. ^{[1
]}

Sayyed, Majid ^{[1
]}

Pachpute, Vipul ^{[1
]}

Phadtare, Ramesh ^{[1
]}

Gole, Gopal ^{[1
]}

Phukan, Samiron ^{[1
]}

Sunkara, Brahmam ^{[1
]}

Samant, Charudatt ^{[1
]}

Shingare, Manisha ^{[1
]}

Naik, Aditya ^{[1
]}

Trivedi, Sneha ^{[1
]}

Marisetti, Ajit Kumar ^{[1
]}

Reddy, Madhusudhan ^{[1
]}

Gholve, Milind ^{[1
]}

Mahajan, Nilesh ^{[1
]}

Sabde, Sudeep ^{[1
]}

Patil, Vinod ^{[1
]}

Modi, Dipak ^{[1
]}

Mehta, Maneesh ^{[1
]}

Nigade, Prashant ^{[1
]}

Tamane, Kaustubh ^{[1
]}

Tota, Swati ^{[1
]}

Goyal, Hemant ^{[1
]}

Volam, Harish ^{[1
]}

Pawar, Shashikant ^{[1
]}

Ahirrao, Prajakta ^{[1
]}

Dinchhana, Lal ^{[1
]}

Mallurwar, Sadanand ^{[1
]}

Akarte, Atul ^{[1
]}

Bokare, Anand ^{[1
]}

Kanhere, Rupesh ^{[1
]}

Reddy, Neetinkumar ^{[1
]}

Koul, Sarita ^{[1
]}

Dandekar, Manoj ^{[1
]}

Singh, Minakshi ^{[1
]}

Bernstein, Peter R. ^{[1
]}

Narasimham, Lakshmi ^{[1
]}

Bhonde, Mandar ^{[1
]}

机构：

[1] Lupin Ltd, Novel Drug Discovery & Dev, Pune 412115, Maharashtra, India

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 23期

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; PI3K INHIBITORS; IDELALISIB; INFLAMMATION; NVP-BYL719; MECHANISMS; AUTOIMMUNE; LYMPHOMA; PATTERNS;

D O I：

10.1021/acs.jmedchem.0c01264

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

PI3K delta inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3K delta 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 PI3K delta 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.

引用

页码：14700 / 14723

页数：24

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