학술논문
Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-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(2H)-one (PF-06821497).
Document Type
Article
Author
Pei-Pei Kung; Bingham, Patrick; Brooun, Alexei; Collins, Michael; Ya-Li Deng; Dinh, Dac; Fan, Connie; Gajiwala, Ketan S.; Grantner, Rita; Gukasyan, Hovhannes J.; Wenyue Hu; Buwen Huang; Kania, Robert; Kephart, Susan E.; Krivacic, Cody; Kumpf, Robert A.; Khamphavong, Penney; Kraus, Manfred; Wei Liu; Maegley, Karen A.
Source
Subject
*DRUG development
*LACTAM derivatives
*DRUG solubility
*HISTONE demethylases
*PHARMACEUTICAL chemistry
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Language
ISSN
0022-2623
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. [ABSTRACT FROM AUTHOR]