Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4 H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models

  • J Med Chem. 2020 Dec 10;63(23):14700-14723. doi: 10.1021/acs.jmedchem.0c01264.
Manojkumar R Shukla  1 Sukanya Patra  1 Mahip Verma  1 Gayathri Sadasivam  1 Nirmal Jana  1 Sachin J Mahangare  1 Prashant Vidhate  1 Dipak Lagad  1 Anand Tarage  1 Murthy Cheemala  1 Chaitanya Kulkarni  1 Shankar Bhagwat  1 Vinod D Chaudhari  1 Majid Sayyed  1 Vipul Pachpute  1 Ramesh Phadtare  1 Gopal Gole  1 Samiron Phukan  1 Brahmam Sunkara  1 Charudatt Samant  1 Manisha Shingare  1 Aditya Naik  1 Sneha Trivedi  1 Ajit Kumar Marisetti  1 Madhusudhan Reddy  1 Milind Gholve  1 Nilesh Mahajan  1 Sudeep Sabde  1 Vinod Patil  1 Dipak Modi  1 Maneesh Mehta  1 Prashant Nigade  1 Kaustubh Tamane  1 Swati Tota  1 Hemant Goyal  1 Harish Volam  1 Shashikant Pawar  1 Prajakta Ahirrao  1 Lal Dinchhana  1 Sadanand Mallurwar  1 Atul Akarte  1 Anand Bokare  1 Rupesh Kanhere  1 Neetinkumar Reddy  1 Sarita Koul  1 Manoj Dandekar  1 Minakshi Singh  1 Peter R Bernstein  1 Lakshmi Narasimham  1 Mandar Bhonde  1 Jayasagar Gundu  1 Rajan Goel  1 Sanjeev Kulkarni  1 Sharad Sharma  1 Rajender Kumar Kamboj  1 Venkata P Palle  1
Affiliations
  • 1. Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
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.