Potent 5-HT4 Receptor Antagonists Research Articles

Acidic biphenyl derivatives: Synthesis and biological activity of a new series of potent 5-HT4 receptor antagonists

Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT4 receptors in the atrium and ventricle of the heart. Recent investigations have revealed increased expression of the 5-HT4(b) isoform in cardiomyocytes of chronic arrhythmic and failing hearts, and that the use of 5-HT4 receptor antagonists may be beneficial for treating these conditions. The 5-HT4 receptor possesses a transmembrane (TM) binding site important for ligand affinity and recognition, as well as a capacity to accommodate bulky ligands. A new series of peripherally-acting 5-HT4 receptor antagonists were prepared by combining the acidic biphenyl group from the class of angiotensin II receptor blockers (ARBs) with the SB207266 (piboserod) scaffold. The new compounds were pharmacologically evaluated and carboxylic acid 21 was identified as a potent and promising 5-HT4 receptor antagonist with moderate affinity for the AT1 receptor. The permeability of carboxylic acid 21 in a Caco-2 assay was low and the corresponding prodrug esters 23a–f were therefore prepared. The pharmacokinetics of methyl ester 20 and n-butyl ester 23c were evaluated in a rat model, revealing incomplete metabolism to carboxylic acid 21. However, methyl ester 20 is a potent 5-HT4 receptor antagonist with binding affinities in the low picomolar range. Methyl ester 20 has promising oral bioavailability and pharmacokinetics and may target 5-HT4 receptors in both CNS and peripheral organs.

Process Development of the Synthetic Route to Sulamserod Hydrochloride

Sulamserod hydrochloride is a potent 5-HT4 receptor antagonist and was a clinical candidate for the treatment of gastrointestinal disorders. Process development of the fairly long synthetic route (12 linear, 14 overall steps) was undertaken. Process improvements were highlighted by aromatic chlorination choices in making dichlorobenzodioxan 2 and acetylaminochloroketone 7, a transfer hydrogenation reducing a nitro group and simultaneous aromatic dechlorination without ketone reduction to give aminoketone 5, and use of the potential mutagenic iodosulfonamide 14 to make quaternary salt 11. The chemistry was scaled-up into pilot plant reactor vessels to produce multikilogram amounts of Sulamserod hydrochloride suitable for drug development.

Synthesis and structure-activity relationships of potent and orally active 5-HT4 receptor antagonists: indazole and benzimidazolone derivatives.

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.