Design and optimization of benzimidazole-containing transient receptor potential melastatin 8 (TRPM8) antagonists
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Table 2
Associated context:
Exploration of the SAR on the isoxazoline scaffold found that substituents in the 2- and 6-positions of the 5-aryl group on the benzimidazole were tolerated (Table 2). The addition of a substituent in the 3-position as in 56 (91 nM) significantly reduced potency compared to the structurally and electronically similar analogues 54 and 55 (1.1 and 2.5 nM, respectively). Hydrophobic substituents at the 2-position generally resulted in single-digit nanomolar antagonists of cTRPM8 (4, 53-55, and 74). Furthermore, polar groups such as the tertiary alcohol of 75 were tolerated, however, the metabolic stability of 75 was poor.
