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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.
Equipment used in this paper: R-Series Flow Chemistry System, Continuously Stirred Tank Reactor (CSTR)
- Phillips DP
- Alper PB
- Borkin D
- Han D
- Kochanek SE
- Gurjar J
- Mathison CJN
- Nelson JM
- Pei W
- Nguyen BN
- Hoffman T
- Okram B
- Nguyen TN
- Jiang S
- Masick BT
- Wang Z
- Cho CY
- Yin H
- Chen Y
- Juarez J
- Jia Y
- Zhou V
- Liu G
- Wright C
- Nguyen T
- Knee DA
- Liu Q
- Liu J
- Li J
- Virata C
- de Oliveira C
- DiDonato M
- Bursulaya B
- Vidal-Biggart A
- Jones DH
- Witmer D
- Chu C
- Jin H
- Herath A
- Richmond W
- Groessl T
- Shapiro M
- Effenberger K
- Arroyo K
- Bretz A
- Honda A
- Gordon WP
- Molteni V
- Haling JR
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
