Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders

Abstract

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

“…A total of 46 PI3Kδ structures have been deposited into the PDB (as of 25 January 2019). In addition to the murine ΔABD-p110δ structure, human p110δ/iSH2 structures have also been published (PDB ID 5T8F, 5UBT, 5VLR), with lower resolution than the ΔABD structures (2.8–2.9 Å) [93,94,95].…”

“…Interactions with δTyr813 and δAsp911 and water interaction networks seem to be key to PI3Kδ potency and selectivity over the other isoforms [108]. Substitutions at the 5-position of a series of pyrrolotriazines that extend into the affinity pocket were able to increase selectivity against the PI3Kγ isoform [93]. Replacement of a 1-(2,2,2-trifluoroethyl)-1-pyrazole ( 25 , PDB ID 5VLR) with a chloro substitution ( 26 ) increased selectivity over PI3Kγ from 37x to 180x.…”

“…Replacement of a 1-(2,2,2-trifluoroethyl)-1-pyrazole ( 25 , PDB ID 5VLR) with a chloro substitution ( 26 ) increased selectivity over PI3Kγ from 37x to 180x. Replacement of the chloro with a trifluoromethyl group ( 27 ) showed similar selectivity over PI3Kγ (Figure 4f) [93].…”

Ribose conversion with amino acids into pyrraline platform chemicals – expeditious synthesis of diverse pyrrole-fused alkaloid compounds

“…Piperazin-2-one is a privileged structural unit in drug discovery because many of the biologically active natural products and the approved drug molecules contain the above scaffold, [46][47][48][49] which exhibit opiate, 50 antiviral, 51 anti-cancer, 52 and anti-diabetes activities 53 as well as treatment effects for immunological disorder 54 and non-Hodgkin's lymphoma. 55 Pyrrole-fused piperazin-2-ones (3 and 4 in Fig.…”

Construction of Highly Functionalized Piperazinones via Post-Ugi Cyclization and Diastereoselective Nucleophilic Addition

“…Piperazinone represents a key structural motif profusely found in drugs and natural products . Hepatitis C virus (HCV) NS4B inhibitor I has been found to possess antiviral activity, whereas compound II is a PI3K-β/δ inhibitor used for the treatment of cancer . Praziquantel III , an anthelmintic drug, is used to treat parasitic worm infections .…”