LY353433, A POTENT, ORALLY EFFECTIVE, LONG-ACTING 5-HT4 RECEPTOR ANTAGONIST - COMPARISON TO CISAPRIDE AND RS23597-190

Although many 5-HT (serotonin, 5-hydroxytryptamine)(4) receptor antago nists have been described, none possess the requisite oral activity an d duration of action for a clinically effective therapeutic agent. The present report identifies LY353433 (1-(1 7)]dec-1-ylcarbon-yl)amino]- 1-piperidinyl]ethyl]-1 H-indazole-3-carboxamide), an indazole amide, a s a high affinity antagonist at the 5-HT, receptor in the rat esophagu s. LY353433 (10(-8), 3 X 10(-8), 10(-7) M) inhibited 5-HT-induced rela xation of carbamylcholine-contracted esophagus with greater potency th an cisapride or RS23597-190, a known 5-HT4 receptor ligand. Furthermor e, RS23597-190 possessed marked agonist activity as did cisapride, whe reas LY353433 did not relax the rat esophagus in concentrations up to 10(-5) M. LY353433 (up to 10(-5) M) did not possess appreciable affini ty for adrenergic, dopaminergic, histaminergic, muscarinic or GABAergi c receptors and, thus, was a highly selective 5-HT4 receptor antagonis t. In addition, LY353433 only slowly associated with and dissociated f rom the 5-HT4 receptor, an attribute that conferred long-lasting 5-HT4 receptor antagonist activity, in contrast to RS23597-190, which rapid ly dissociated from the 5-HT4 receptor. LY353433 dose-dependently inhi bited 5-HT4 receptor-mediated ex vivo relaxation in the rat esophagus after either i.v. (0.1, 0.3 and 1.0 mg/kg) or p.o. (0.1, 0.3, 1.0 and 3.0 mg/kg) administration. Furthermore, the p.o. to i.v. dose ratio wa s approximately one, suggesting that LY353433 was well absorbed with e xcellent pharmacodynamics in the rat. LY353433 (0.3 mg/kg p.o.) blocke d esophageal 5-HT4 receptors ex vivo through 6 hr after p.o. dosing wi th responses returning to control by 16 hr, indicative of long duratio n receptor blockade. Lastly, in rats LY353433 was exceptionally safe b ecause acute doses up to 300 mg/kg p.o. did not result in either sympt oms or deaths. Thus, LY353433 is a potent, selective, orally effective , long-acting and safe 5-HT4 receptor antagonist that is highly suitab le for clinical use.