Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of replacement of the 3-hydroxyphenyl group with pyridine or thiophene bioisosteres
The potent and selective KOR antagonist JDTic was derived from the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine class of pure opioid antagonists. In previous studies we reported that compounds that did not have a hydroxyl on the 3-hydroxyphenyl group and did not have methyl groups at the 3- and 4-position of the piperidine ring were still potent and selective KOR antagonists. In this study we report JDTic analogs 2, 3a-b, 4a-b, and 5, where the 3-hydroxyphenyl ring has been replaced by a 2-, 3-, or 4-pyridyl or 3-thienyl group and do not have the 3-methyl or 3,4-dimethyl groups, remain potent and selective KOR antagonists. Of these, (3R)-7-hydroxy-N-(1S)-2-methyl-[4-methyl-4-pyridine-3-ylcarboxamide (3b) had the best overall binding potency and selectivity in a [S-35] GTP gamma S functional assay, with a K-e = 0.18 nM at the KOR and 273- and 16,700-fold selectivity for the KOR relative to the MOR and DOR, respectively. Calculated physiochemical properties for 3b suggest that it will cross the blood-brain barrier. (C) 2016 Elsevier Ltd. All rights reserved.
Kormos, C. M., Gichinga, M. G., Runyon, S. P., Thomas, J. B., Mascarella, S. W., Decker, A. M., ... Carroll, F. I. (2016). Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of replacement of the 3-hydroxyphenyl group with pyridine or thiophene bioisosteres. Bioorganic and Medicinal Chemistry, 24(16), 3842-3848. DOI: 10.1016/j.bmc.2016.06.029