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DOI 10.1021/acs.jmedchem.6c01454

Медицинская библиотека · Journal of medicinal chemistry · 2026

Lead Optimization of Multimutant KRAS Switch-II Pocket Macrocyclic Inhibitors via Isosteric Replacement to Improve ADME and Oral Exposure.

Phillips Dean P, Alper Phil B, Borkin Dmitry, Han Dong, Kochanek Sarah E, Gurjar Jitendra, Mathison Casey J N, Nelson John M, Pei Wei, Nguyen Bao Ngoc, Hoffman Timothy, Okram Barun, Nguyen Truc N, Jiang Songchun, Masick Brian T, Wang Zhicheng, Cho Charles Y, Yin Hong, Chen Yu, Juarez Jose, Jia Yong, Zhou Vicki, Liu Guoxun, Wright Clifford, Nguyen Trish, Knee Deborah A, Liu Qian, Liu Jun, Li Jie, Virata Cyrus, de Oliveira Cesar, DiDonato Michael, Bursulaya Badry, Vidal-Biggart Agnes, Jones David H, Witmer Darbi, Chu Carolyn, Jin Hong, Herath Ananda, Richmond Wendy, Groessl Todd, Shapiro Michael, Effenberger Kathleen, Arroyo Konrad, Bretz Angela, Honda Ayako, Gordon William P, Molteni Valentina, Haling Jacob R

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Аннотация

Starting from our internally discovered, potent panKRAS inhibitor BRSD-143 (1), we executed a targeted bioisosteric optimization of the naphthol and fluoropyrrolizidine motifs to preserve (or increase) KRAS pan-inhibitory potency while improving DMPK/ADME liabilities. These studies delivered 12 (BRSD-212), a highly potent and efficacious lead in which (2-azabicyclo[4.2.0]octan-6-yl)methanol (ABO) serves as a bioisostere for the widely deployed 2-fluoropyrrolizidine substituent. In parallel, replacement of the naphthol moiety with an indazole afforded 21, which demonstrated improved pharmacokinetic performance and ADME characteristics by mitigating glucuronidation-mediated clearance as the dominant metabolic pathway.

Для цитирования: Phillips Dean P, Alper Phil B, Borkin Dmitry, Han Dong, Kochanek Sarah E, Gurjar Jitendra, Mathison Casey J N, Nelson John M, Pei Wei, Nguyen Bao Ngoc, Hoffman Timothy, Okram Barun, Nguyen Truc N, Jiang Songchun, Masick Brian T, Wang Zhicheng, Cho Charles Y, Yin Hong, Chen Yu, Juarez Jose, Jia Yong, Zhou Vicki, Liu Guoxun, Wright Clifford, Nguyen Trish, Knee Deborah A, Liu Qian, Liu Jun, Li Jie, Virata Cyrus, de Oliveira Cesar, DiDonato Michael, Bursulaya Badry, Vidal-Biggart Agnes, Jones David H, Witmer Darbi, Chu Carolyn, Jin Hong, Herath Ananda, Richmond Wendy, Groessl Todd, Shapiro Michael, Effenberger Kathleen, Arroyo Konrad, Bretz Angela, Honda Ayako, Gordon William P, Molteni Valentina, Haling Jacob R. Lead Optimization of Multimutant KRAS Switch-II Pocket Macrocyclic Inhibitors via Isosteric Replacement to Improve ADME and Oral Exposure.. Journal of medicinal chemistry. 2026. DOI: 10.1021/acs.jmedchem.6c01454.

Предметные рубрики MeSH

HumansAnimalsStructure-Activity RelationshipProto-Oncogene Proteins p21(ras)Macrocyclic CompoundsBioisosterismAdministration, OralRats
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