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Optimization of Versatile Oxindoles as Selective PI3Kδ Inhibitors.

ABSTRACT: The 3,3-disubstituted oxindole moiety is a versatile and rigid three-dimensionally shaped scaffold. When engineered with a purine hinge-binding core, exceptionally selective PI3Kδ kinase inhibitors were discovered by exploiting small differences in isoform selectivity pockets. Crystal structures of early lead 2f bound to PI3Kδ and PI3Kα helped rationalize the high selectivity observed with 2f. By attenuating the lypophilicity and metabolic liabilities of an oxindole moiety, we improved the preclinical species PK and solubility and reduced adenosine uptake activity. The excellent potency and kinome selectivity of 7-azaoxindole 4d and spirooxindole 5d, together with a low plasma clearance and good half-life in rat and dog, supported a low once-daily predicted human dose.

SUBMITTER: Methot JL

PROVIDER: S-EPMC7734802 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Optimization of Versatile Oxindoles as Selective PI3Kδ Inhibitors.

Methot Joey L JL Achab Abdelghani A Christopher Matthew M Zhou Hua H McGowan Meredeth A MA Trotter B Wesley BW Fradera Xavier X Lesburg Charles A CA Goldenblatt Peter P Hill Armetta A Chen Dapeng D Otte Karin M KM Augustin Martin M Shah Sanjiv S Katz Jason D JD

ACS medicinal chemistry letters 20201119 12

The 3,3-disubstituted oxindole moiety is a versatile and rigid three-dimensionally shaped scaffold. When engineered with a purine hinge-binding core, exceptionally selective PI3Kδ kinase inhibitors were discovered by exploiting small differences in isoform selectivity pockets. Crystal structures of early lead <b>2f</b> bound to PI3Kδ and PI3Kα helped rationalize the high selectivity observed with <b>2f</b>. By attenuating the lypophilicity and metabolic liabilities of an oxindole moiety, we impr ...[more]

PMID: 33335668

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