Bioorganic & Medicinal Chemistry Letters · 2022 · 11 citations · 12 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryStructure-activity RelationshipsHit-to-lead OptimizationLead Compound DesignLead DiscoveryLigand-based DesignPotency OptimizationTyrosine Kinase InhibitorsChemical Structure-activity RelationshipsIn Vivo StudiesKinase InhibitorsProtein Kinase InhibitorsSelective Tyrosine Kinase InhibitorsSelectivityStructure-based Lead DiscoveryStructure-guided Lead Discovery
Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified displaying high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-α, PDGFR-β, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.
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