A novel class of aryl alkynylthiophene compounds has been designed to target peripheral CB1R to eliminate/minimize CNS side effects as observed with 1, a typical brain CBlR-acting agent. The titled compound, l-(2,4-dichlorophenyl)-4-ethyl-5-(5-(2-(4-(trifluoromethyl)phenyl)ethynyl)thiophen-2 -yl)-N(piperidin-l-yl)-lH-pyrazole-3-carboxamide (8), is tentatively y recognhized as a peripheral inverse agonist based on its negative central effects in CB1R agonist-induced hypothermia and analgesia models, and low brain exposure (B/P = 1/33) measured at a time point of 2 hours following oral administration. The chronic study of 8 in DIO mice is currently underway. A full account of the in vivo studies, with particular emphasis on addressing issues of central drug accumulation and peripheral metabolic benefits, as well as further SAR studies on the series will be reported elsewhere in due course.
