Indazole partial agonists targeting peripheral cannabinoid receptors

Considerable efforts have been made to produce full agonists of cannabinoid receptors (CBRs), but there has been limited reports on partial agonists and the associated structure activity relationship (SAR) studies. Partial agonists of peripheral CBRs may have unique pharmacological profiles that provide prolonged efficacy through delayed or limited development of tolerance, absent or limited psychiatric effects, and good therapeutic index. Some potential therapeutic applications include inflammatory diseases, gastrointestinal (GI) disorders and pain. In this report, we show the SAR developed in the conversion of indazole full agonists to peripheral partial agonists. Compound 45 is a partial agonist of CBRs with 50% Effective Concentration (EC₅₀) of ∼150 nM at human (h)CB1 and 35 nM at hCB2 along with % Maximum Efficacy (E_max) of ∼32 at hCB1 and ∼17 at hCB2 respectively. This compound demonstrated peripheral selectivity and oral absorption in mouse pharmacokinetic (PK) studies with a half-life of ∼7.3 h in plasma and <10% brain penetrance.