Design, Synthesis, and Pharmacological Evaluation of Piperidin-4-yl amino aryl sulfonamides: Novel, Potent, Selective, Orally Active, and Brain Penetrant 5‑HT₆ Receptor Antagonists

Our initial findings around aryl sulfonamide series led to <i>N</i>-(3,5-dichloro-2-methoxyphenyl)-3-(1-methylpiperidin-4-ylamino)-4-methoxy benzenesulfonamide as potent and selective 5-HT₆ receptor (5-HT₆R) antagonist with reasonable pharmacokinetic properties and activity in animal models of cognition. However, lack of brain penetration and P-glycoprotein liability makes this scaffold unsuitable for further development. Our goal was to identify small molecule 5-HT₆R antagonist with adequate brain penetration, acceptable ADME properties, no P-glycoprotein, and no hERG liability. Several structural modifications including bringing conformational constraint around the sulfonamide −NH group and introduction of a heteroatom to modulate the physicochemical properties were attempted. This effort culminated in the discovery of series of novel, potent, selective, orally bioavailable, and adequately brain penetrant compounds with no hERG liability. These compounds showed activity in animal models of cognition like object recognition task and water maze and in brain microdialysis studies at lower doses

Discovery and Development of 1‑[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]‑1<i>H</i>‑indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT₆) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease

Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT₆R) antagonists resulted in identification of 1-[(2-bromophenyl)­sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)­methyl]-1<i>H</i>-indole dimesylate monohydrate (<b>5al</b>, SUVN-502) as a clinical candidate for potential treatment of cognitive disorders. It has high affinity at human 5-HT₆R (<i>K</i>_i = 2.04 nM) and selectivity over 100 target sites which include receptors, enzymes, peptides, growth factors, ion channels, steroids, immunological factors, second messengers, and prostaglandins. It has high selectivity over 5-HT_2A receptor. It is orally bioavailable and brain penetrant with robust preclinical efficacy. The combination of <b>5al</b>, donepezil, and memantine (triple combination) produces synergistic effects in extracellular levels of acetylcholine in the ventral hippocampus. Preclinical efficacy in triple combination and high selectivity over 5-HT_2A receptors are the differentiating features which culminated in selection of <b>5al</b> for further development. The Phase-1 evaluation of safety and pharmacokinetics has been completed, allowing for the initiation of a Phase-2 proof of concept study