title: Synthesis and structure-activity relationships of potent and orally active 5-HT4 receptor antagonists: indazole and benzimidazolone derivatives.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Schaus
authors.forename: D C
authors.initials: DC
authors.lastname: Thompson
authors.forename: W E
authors.initials: WE
authors.lastname: Bloomquist
authors.forename: A D
authors.initials: AD
authors.lastname: Susemichel
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: M L
authors.initials: ML
authors.lastname: Cohen
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004947:Esophagus / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007191:Indazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000317:Adrenergic alpha-Antagonists; D007191:Indazoles; C099140:LY 353433; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D044422:Receptors, Serotonin, 5-HT4; D000218:Adamantane