MetID Guided Drug Design
MetID guided target design is the topic of our paper pick for February, published by Li and colleagues at Merck. There are multiple facets to the story, of which only a selection are highlighted below.
Interesting was the introduction of a hydroxyl group to improve polarity but which also had a positive effect on the off-target profile. To curb O-glucuronidation at that position, a gem-dimethyl group was incorporated, which not only boosted metabolic stability but also resulted in increased potency of “compound 17”.
An earlier example of how to manage glucuronidation by steric hindrance is illustrated in “compound 25” in the paper by Zhang et al., where introduction of a hydroxyl adjacent to the carboxylate moiety mitigated the risk of acyl glucuronidation.
Hongjun Zhang, Blair T. Lapointe, Neville Anthony, Rita Azevedo, Jos Cals, Craig C. Correll, Matthew Daniels, Sujal Deshmukh, Hans van Eenenaam, Heidi Ferguson, Laxminarayan G. Hegde, Willem Jan Karstens, John Maclean, J. Richard Miller, Lily Y. Moy, Vladimir Simov, Sunil Nagpal, Arthur Oubrie, Rachel L. Palte, Gopal Parthasarathy, Nunzio Sciammetta, Mario van der Stelt, Janice D. Woodhouse, B. Wesley Trotter, and Kenneth Barr
ACS Medicinal Chemistry Letters 2020 11 (2), 114-119. DOI: 10.1021/acsmedchemlett.9b00431
Derun Li, David L. Sloman, Abdelghani Achab, Hua Zhou, Meredeth A. McGowan, Catherine White, Craig Gibeau, Hongjun Zhang, Qinglin Pu, Indu Bharathan, Brett Hopkins, Kun Liu, Heidi Ferguson, Xavier Fradera, Charles A. Lesburg, Theodore A. Martinot, Ji Qi, Zhiguo J. Song, Jingjun Yin, Huangguang Zhang, Licheng Song, Baoqiang Wan, Suzanne DAddio, Nicolas Solban, J. Richard Miller, Beata Zamlynny, Alan Bass, Elizabeth Freeland, Bridget Ykoruk, Catherine Hilliard, Jude Ferraro, Jin Zhai, Ian Knemeyer, Karin M. Otte, Stella Vincent, Nunzio Sciammetta, Alexander Pasternak, David Jonathan Bennett, and Yongxin Han
Journal of Medicinal Chemistry 2022 65 (8), 6001-6016. DOI: 10.1021/acs.jmedchem.1c01670