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- W2775830266 abstract "A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding." @default.
- W2775830266 created "2017-12-22" @default.
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- W2775830266 date "2017-12-27" @default.
- W2775830266 modified "2023-10-18" @default.
- W2775830266 title "Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (<i>R</i>)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2<i>H</i>)-one (PF-06821497)" @default.
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- W2775830266 doi "https://doi.org/10.1021/acs.jmedchem.7b01375" @default.
- W2775830266 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29211475" @default.
- W2775830266 hasPublicationYear "2017" @default.
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