Structure–Activity Relationship of Imidazopyridinium Analogues as Antagonists of Neuropeptide S Receptor

Abstract

The discovery and characterization of a novel chemical series of phosphorothioyl-containing imidazopyridines as potent Neuropeptide S Receptor antagonists is presented. The synthesis of analogs and their SAR with respect to the Gq, Gs, and ERK pathways is detailed. Pharmacokinetics and in vivo efficacy of a potent analog in a food intake rodent model are also included underscoring its potential therapeutic value for the treatment of sleep, anxiety, and addiction disorders.

Rapid, metal-free and aqueous synthesis of imidazo[1,2-a]pyridine under ambient conditions

“…27,28 This reaction has been applied by Marugan et al to generate a wide range of imidazopyridinium analogues as antagonists of neuropeptide S receptor. 29 Further functionalisations at the methyl position (R 2 in Scheme 1) are also well established. [30][31][32][33][34] We were particularly interested in the cyclisation step, which was proposed to be catalysed by the Pd catalyst.…”

Palladium‐Catalyzed Oxidative Cyclization for the Synthesis of 2‐Alkylimidazo[5,1,2‐cd]indolizines

“…Photoluminescence spectra were recorded with a Cary Eclipse Fluorescence spectrophotometer. Compound 2a , 2b , and 2c were prepared following a literature procedure of similar compounds …”

Pharmacology, Physiology and Genetics of the Neuropeptide S System

“…Details about synthesis and pharmacological activities can be found in the original literature. SHA 68 [ 18 ], RTI-118 [ 68 ], PI1 [ 118 ], MLS001018695 [ 119 ], NCGC84 [ 23 ], QA1 [ 120 ], R06039-478 [ 121 ].…”

“…Based on preclinical data, such compounds may have therapeutic potential as sleep medications or in the treatment of drug addiction, especially to prevent relapse of drug abuse [23,25,68,117]. [18], RTI-118 [68], PI1 [118], MLS001018695 [119], NCGC84 [23], QA1 [120], R06039-478 [121].…”