1-[2-(1-Cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one: a Histamine H Receptor Inverse Agonist with Efficacy in Animal Models of Cognition.

A series of chemical optimizations, which was guided by in vitro affinity at histamine H receptor (H R), modulation of lipophilicity, ADME properties and preclinical efficacy resulted in the identification of 1-[2-(1-cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one (45 e) as a potent and selective (K =4.0 nM) H R inverse agonist. Dipsogenia induced by (R)-α-methylhistamine was dose dependently antagonized by 45 e, confirming its functional antagonism at H R.

Discovery and Development of N-[4-(1-Cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide Dihydrochloride (SUVN-G3031): A Novel, Potent, Selective, and Orally Active Histamine H Receptor Inverse Agonist with Robust Wake-Promoting Activity.

A series of chemical optimizations guided by in vitro affinity at a histamine H receptor (HR), physicochemical properties, and pharmacokinetics in rats resulted in identification of N-[4-(1-cyclobutyl-piperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide dihydrochloride (17v, SUVN-G3031) as a clinical candidate. Compound 17v is a potent (hHR K = 8.73 nM) inverse agonist at HR with selectivity over other 70 targets, Compound 17v has adequate oral exposures and favorable elimination half-lives both in rats and dogs.

Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT) 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-HTR) antagonists resulted in identification of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (5al, SUVN-502) as a clinical candidate for potential treatment of cognitive disorders. It has high affinity at human 5-HTR (K = 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.

Design, synthesis and pharmacological evaluation of indolylsulfonamide amines as potent and selective 5-HT6 receptor antagonists.

A series of N'-[3-(indole-1-sulfonyl) aryl]-N,N-dimethyl ethane-1,2-diamines and N'-[3-(indole-1-sulfonyl) aryl]-N,N-dimethyl propane-1,3-diamines was designed and synthesized as 5-HT6 receptor ligands. These compounds, when screened in a functional reporter gene-based assay, displayed potent antagonistic activity with Kb values in the range of 1.8-60 nM.

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 N-(3,5-dichloro-2-methoxyphenyl)-3-(1-methylpiperidin-4-ylamino)-4-methoxy benzenesulfonamide as potent and selective 5-HT(6) receptor (5-HT(6)R) 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-HT(6)R antagonist with adequate brain penetration, acceptable ADME properties, no P-glycoprotein, and no hERG liability.

Design, synthesis and preliminary screening of novel 3-(2-N,N-dimethylaminoethylthio) indole derivatives as potential 5-HT(6) receptor ligands.

The synthesis and potential 5-hydroxytryptamine(6) receptor (5-HT6R) antagonist activity of a novel series of N-arylsulfonyl-3-(2-N,N-dimethylaminoethylthio) indoles has been reported. The molecular modeling, synthesis and in-vitro radioligand binding data of this series are discussed. The present article describes 37 derivatives of the title series.