1. Academic Validation
  2. 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

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

Affiliation

  • 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.

Figures