DISCOVERY OF AN ORALLY BIOAVAILABLE NK1 RECEPTOR ANTAGONIST, -TETRAZOL-1-YLBENZYL)(2-PHENYLPIPERIDIN-3-YL)AMINE (GR203040), WITH POTENT ANTIEMETIC ACTIVITY

The antiemetic, pharmacokinetic, and metabolic profile of CP-99,994, a potent NK1 receptor antagonist, has been carefully evaluated. As a re sult we began a medicinal chemistry program which initially identified a 3-furanyl analogue (6) with improved antiemetic potency and a methy l sulfone (5) with enhanced metabolic stability and oral bioavailabili ty. The improved pharmacokinetic profile of methyl sulfone (5) was ass ociated with its low lipophilicity, and a therefore a number of hetero cyclic analogues with reduced log D were synthesized. Out of this prog ram emerged 19 (GR203040), a tetrazolyl-substituted analogue. Tetrazol e 19 inhibits radiation-induced emesis in the ferret with high potency when administered both subcutaneously and orally, has a long duration of action, and has high oral bioavailability in the dog. Tetrazole 19 is currently undergoing evaluation as a novel approach for the contro l of emesis associated with, for example, cancer chemotherapy.