Projected Dose Optimization of Amino- and Hydroxypyrrolidine Purine PI3Kδ Immunomodulators.
Joey L MethotHua ZhouMeredeth A McGowanNeville John AnthonyMatthew ChristopherYudith GarciaAbdelghani AchabKathryn LipfordBenjamin Wesley TrotterMichael D AltmanAndreas VerrasCharles A LesburgChaomin LiStephen AlvesCraig P ChappellRenu JainRuban MangadoElaine PinheiroSybill M G WilliamsPeter GoldenblattArmetta HillLynsey ShafferDapeng ChenVincent TongRobbie L McLeodHyun-Hee LeeHongshi YuSanjiv ShahJason D KatzPublished in: Journal of medicinal chemistry (2021)
The approvals of idelalisib and duvelisib have validated PI3Kδ inhibitors for the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our program led to the identification of structurally distinct heterocycloalkyl purine inhibitors with excellent isoform and kinome selectivity; however, they had high projected human doses. Improved ligand contacts gave potency enhancements, while replacement of metabolic liabilities led to extended half-lives in preclinical species, affording PI3Kδ inhibitors with low once-daily predicted human doses. Treatment of C57BL/6-Foxp3-GDL reporter mice with 30 and 100 mg/kg/day of 3c (MSD-496486311) led to a 70% reduction in Foxp3-expressing regulatory T cells as observed through bioluminescence imaging with luciferin, consistent with the role of PI3K/AKT signaling in Treg cell proliferation. As a model for allergic rhinitis and asthma, treatment of ovalbumin-challenged Brown Norway rats with 0.3 to 30 mg/kg/day of 3c gave a dose-dependent reduction in pulmonary bronchoalveolar lavage inflammation eosinophil cell count.
Keyphrases
- regulatory t cells
- cell proliferation
- pi k akt
- allergic rhinitis
- endothelial cells
- signaling pathway
- high resolution
- climate change
- dendritic cells
- cell therapy
- single cell
- type diabetes
- stem cells
- crispr cas
- physical activity
- mass spectrometry
- cell cycle
- adipose tissue
- skeletal muscle
- air pollution
- photodynamic therapy
- peripheral blood
- high fat diet induced