A series of indole-3-carboxamides, indazole-3-carboxamides, and benzimidazolone-3-carboxamides was synthesized and evaluated for antagonist affinity at the 5-HT4 receptor in the rat esophagus. The endo-3-tropanamine derivatives in the indazole and benzimidazolone series possessed greater 5-HT4 receptor affinity than the corresponding indole analogues. 5-HT4 receptor antagonist affinity was further increased by alkylation at N-1 of the aromatic heterocycle. In a series of 1-isopropylindazole-3-carboxamides, replacement of the bicyclic tropane ring system with the monocyclic piperidine ring system or an acyclic aminoalkylene chain led to potent 5-HT4 receptor antagonists. In particular, those systems in which the basic amine was substituted with groups capable of forming hydrogen bonds showed increased 5-HT4 receptor antagonist activity. While some of these compounds displayed high affinity for other neurotransmitter receptors (in particular, 5-HT3, alpha1, and 5-HT2A receptors), as the conformational flexibility of the amine moiety increased, the selectivity for the 5-HT4 receptor also increased. From this series of compounds, we identified LY353433 (1-(1-methylethyl)-N-[2-[4-[(tricyclo[3.3.1.1(3, 7)]dec-1-ylcarbonyl)amino]-1-piperidinyl]ethyl]-1H-indazole-3- carboxamide) as a potent and selective 5-HT4 receptor antagonist with clinically suitable pharmacodynamics.

Indazoles as Indole Bioisosteres: Synthesis and Evaluation of the Tropanyl Ester and Amide of IndazoIe-3-carboxylate as Antagonists at the Serotonin 5HT3 Receptor

1 The in vitro activity of four aryl propanolamines was compared to two prototypic b 3 receptor agonists, CGP 12177 and CL316243 at the human b 3 receptor, the rat b 3 receptor in the stomach fundus and receptors mediating atrial tachycardia. 2 L-739,574 was the most potent (EC 50 =9 nM) and selective agonist at the human b 3 receptor with high maximal response (74% of the maximal response to isoproterenol). 3 A phenol-biaryl ether analogue possessed modest anity for the human b 3 receptor (EC 50 =246 nM), but was highly ecacious with a maximal response 82% of the maximal response to isoproterenol. The other derivatives were intermediate in potency with low maximal responses. 4 These agonists at the human b 3 receptor did not activate the rat b 3 receptor in the rat stomach fundus. In fact, the aryl propanolamines (10 76 M) inhibited CL316243-induced activation of the rat b 3 receptor. Thus, agonist activity at the human b 3 receptor translated into antagonist activity at the rat b 3 receptor. 5 L739,574 and the phenol biaryl ether increased heart rate via b 1 receptors. 6 Although CGP12177 produced atrial tachycardia, neither the indole sulphonamide nor biphenyl biaryl ether did, although both had high anity for the human b 3 receptor. Thus, the atrial tachycardic receptor was not identical to the human b 3 receptor. 7 These studies (a) characterized four aryl propanolamines with high anity at the human b 3 receptor, (b) found that they were antagonists at the rat b 3 receptor, an observation with profound implications for in vivo rat data, and (c) established that the rodent atrial non-b 1 , b 2 or b 3 tachycardic receptor was also unrelated to the human b 3 receptor.

No abstract

Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.