3-ARYL-1,2-DIACETAMIDOPROPANE DERIVATIVES AS NOVEL AND POTENT NK-1 RECEPTOR ANTAGONISTS

Early structure-activity studies on racemic tryptophan ester and amide NK-1 antagonists 5-7 led to the discovery that the potency of the ser ies could be markedly increased by moving the carbonyl function in the se molecules to an off-chain position as in the 3-aryl-1,2-diacetamido propane 9. Further medicinal chemistry incorporating this change resul ted in the discovery of a novel series of highly potent aryl amino aci d derived NK-1 antagonists of the R stereoisomeric series (IC50's = 10 0 pM to >5 mu M). Compounds in this series were shown to be competitiv e antagonists using an in. vitro NK-1 smooth muscle assay, and this da ta correlated well with observed human NK-1 binding affinities. Two of these agents, (R)-25 and (R)-32, blocked intrathecal NK-1 agonist-dri ven [Ac-[Arg(6), Sar(9), Met(O-2)(11)]-substance P 6-11 (Ac-Sar(9))] n ociceptive behavior in mice. Both compounds potently blocked the neuro genic dural inflammation following trigeminal ganglion stimulation in the guinea pig after intravenous administration. Further, upon oral ad ministration in this model, (R)-32 was observed to be very potent (ID5 0 = 91 ng/kg) and have a long duration of action (>8 h at 1 mu g/kg). Compound (R)-32, designated LY303870, is currently under clinical deve lopment as an NK-1 antagonist with a long duration of action.