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

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.

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions

“…Additionally, 44 displayed better TGI than 1 in ABC-diffuse large B cell lymphoma (DLBCL) (TMD-8 and OCI-Ly10) and GCB-DLBCL (SU-DHL-6, TGI = 55% and 38% of 44 and 1 at the dose of 5 mg/kg, respectively) xenograft mouse models. 135 In light of the functions of both PI3Kγ and PI3Kδ in hematopoietic cells, it may be interesting to design molecules that combine these functions in one compound. Compound 45, the result of modification on 1, is a novel PI3Kδ/γ inhibitor with a seven-membered spirocyclic spacer bearing 2,4-diaminopyrimidine-5-carbonitrile.…”

“…Compound 44 showed superior anticancer activities against TMD-8, OCI-Ly10, and SU-DHL-6 cell lines with IC 50 values <0.1 nM. Additionally, 44 displayed better TGI than 1 in ABC-diffuse large B cell lymphoma (DLBCL) (TMD-8 and OCI-Ly10) and GCB-DLBCL (SU-DHL-6, TGI = 55% and 38% of 44 and 1 at the dose of 5 mg/kg, respectively) xenograft mouse models …”

Catalytic Photoredox C–H Arylation of 4-Oxo-4H-pyrido[1,2-a]pyrimidine-3-diazonium Tetrafluoroborates and Related Heteroaryl Diazonium Salts

“…They are associated with 21 different bioindicators, such as cardiovascular- (416), , antitumor- (374), , nervous system- (321), , anti-inflammatory (306), , and anti-infective agents (284). , As many of these heterocyclic systems are fluorescent, they are also suitable for fluorescent sensing and labeling . Some examples of biologically active 3-aryl-4 H -quinolizine-4-one , and 3-aryl-4 H -pyrido­[1,2- a ]­pyrimidin-4-one derivatives, including the anti-allergic drug pemirolast are depicted in Figure .…”

Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma

“… For instance, Idelalisib is a type of propeller-shaped inhibitor that is core-structured with quinazolin-4­(3 H )-one, and until now, there has been extensive medicinal chemistry exploration of chemotypes that give propeller-shaped structures for differential therapies. − Despite these advances, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy remains continuous interesting and important. During the course of our efforts in drug discovery and HCC therapy, − we started our exploration for PI3Kδ inhibitors by looking for a novel propeller-shaped chemotype via a scaffold-hopping strategy to replace quinazolin-4­(3 H )-one of Idelalisib. − Hence, we identified indazole as a new and suitable core to be potent, propeller-shaped, and selective PI3Kδ inhibitor . A total of 26 novel indazoles were designed and prepared to identify compound 9x , which exhibits good isoform selectivity, pharmaceutical profile, and a notably superior efficacy toward HCC compared to Idelalisib and Sorafenib.…”