Projected Dose Optimization of Amino- and Hydroxypyrrolidine Purine PI3Kδ Immunomodulators

Abstract

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.

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury

“…For example, compounds 29, 30, and 31 showed good inhibitory activities against PI3Kδ and also exhibited remarkable anti-inflammatory activities. At this stage, those compounds with slight toxicity (cell viability below 80% at 10 μM) were excluded for further tests (Figure S1), 13 including compounds 23,26,33,34,38,39, and 42−46. Next, we took together the PI3Kδ potency, anti-inflammatory activity, and toxicity, and selected compounds 29, 30, 31, and 36 as promising candidates for further multidose evaluation.…”

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

“…In September 2018, the FDA approved 8f for the treatment of patients with CLL/SLL or relapsed/refractory follicular lymphoma (FL) [ 142 ]. 8f is structurally similar to 8e and is also an ATP-competitive inhibitor discovered through a structure-based optimization approach [ 84 , 150 , 151 , 152 ]. The -F on 8e ’s isoquinolone is substituted with -Cl and the ethyl group is reduced to methyl to obtain the dual potent inhibitor of PI3Kδ/γ 8f .…”

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

“…MSD-496486311 ( 38 ) is a selective PI3Kδ inhibitor (IC 50 values of 180, 1600, 1.2, and 4400 nM against PI3Kα, β, δ, and γ, respectively) bearing a heterocycloalkyl purine group, which forms an H-bond with Val828 (Figure A) . Compound 38 showed good PK profiles (clearance: 4.3 mL/min/kg in Beagle dogs and 8.1 mL/min/kg in Wistar Han rats; t 1/2 = 4.7 h in Beagle dogs and 2.7 h in Wistar Han rats; F = 95% in Beagle dogs and 55% in Wistar Han rats).…”

“…In C57BL/6-Foxp3-GDL reporter mice, 38 could lead to a 70% reduction in the number of Foxp3-expressing regulatory T cells. In ovalbumin-challenged Brown Norway rats for allergic rhinitis and asthma, the oral administration of 38 (0.3–30 mg/kg) reduced the pulmonary bronchoalveolar lavage inflammation eosinophil cell count in a dose-dependent manner …”

“…128 36 exhibited a potent effect MSD-496486311 ( 38) is a selective PI3Kδ inhibitor (IC 50 values of 180, 1600, 1.2, and 4400 nM against PI3Kα, β, δ, and γ, respectively) bearing a heterocycloalkyl purine group, which forms an H-bond with Val828 (Figure 6A). 130 Compound 38 130 Compound 39 (IC 50 values of 4400, 44,000, 3.8, and 4200 nM against PI3Kα, β, δ, and γ, respectively) is a selective PI3Kδ inhibitor by linking an oxindole moiety to the hinge-binding core of 1. 131 The 7-azaoxindole selectivity motif was well tolerated, and the increased polarity further improved selectivity versus adenosine uptake.…”