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)
| Autor: | Michael R. Collins, Robert Steven Kania, Connie Fan, Sutton Scott Channing, Dominique Verhelle, Kephart Susan Elizabeth, Martin James Wythes, Shuiwang Wang, Karen A. Maegley, Lisa Nguyen, Daniel Tyler Richter, A.E. Stewart, Pei-Pei Kung, Buwen Huang, Shikhar Sharma, Shinji Yamazaki, Ya-Li Deng, Rita Grantner, Patrick Bingham, Robert Arnold Kumpf, Penney Khamphavong, Jinjiang Zhu, Dac M. Dinh, Manfred Kraus, Wei Liu, Sean Uryu, Jillian E. Spangler, Wenyue Hu, Hui Wang, Robert A. Rollins, Cody Krivacic, Zehnder Luke Raymond, Neal W. Sach, Alexei Brooun, John Sherrill, Shijian Ren, Martin A. Edwards, Huichun Zhu, Ketan S. Gajiwala, Shuibo Xin, Hovhannes J. Gukasyan |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 61:650-665 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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-pr... |
| Databáze: | OpenAIRE |
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