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.