Aminoalkoxybiphenylnitriles as Histamine‐3 Receptor Ligands.

Abstract

Receptor binding activityReceptor binding activity X 0280 Aminoalkoxybiphenylnitriles as Histamine-3 Receptor Ligands. -Based on the preceding synthesis and testing of a series of related compounds, (I) is found to show high affinity for human histamine H 3 receptors coupled with other favorable physiological and pharmacodynamic properties. The results suggest that such compounds may have therapeutic potential in various human diseases. -(FAGHIH*, R.; DWIGHT, W.; VASUDEVAN, A.; DINGES, J.; CONNER, S. E.; ESBENSHADE, T. A.; BENNANI, Y. L.; HANCOCK, A. A.; Bioorg. Med. Chem. Lett. 12 (2002) 21, 3077-3079; Neurosci. Res., Global Pharm. Res. Dev., Abbott Lab., Abbott Park, IL 60031, USA; Eng.) -M. Bohle 09-210

The medicinal chemistry of novel H 3 antagonists

“…The 4-cyanophenyl group has appeared in other non-imidazole series [4,8], and also showed high potency in the benzofuran series, especially when appropriately incorporated into the 5-or 6-position of the benzofuran ring. The benzofurans had about equal or greater potency than the closest homologous acyclic biphenyl-nitrile propyloxyamine analogs in 5 of 8 cases.…”

Histamine H 3 antagonists in models of obesity

“…Therefore, we evaluated the non-imidazolebased H 3 antagonist A-331440 ({4¢-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile}, Fig. 1 [7]) in diet-induced or genetic (ob/ob) mouse obesity models. …”

Structure-activity relationships of A-331440: a new histamine-3 antagonist with anti-obesity properties

“…Compound (2) was prepared as described by Faghih [2]. N-alkyls, acyls, amides, sulfonamides and urea analogs were prepared using standard acylation chemistry to give compounds 3 -20.…”

“…Recently we demonstrated that aminoalkoxybiphenylnitriles such as A-331440 (1) are potent non-imidazole histamine H 3 -receptor antagonists [2]. The H 3 antagonist A-331440 decreases body weight, body fat content and improves insulin sensitivity in models of obesity in rodents [3].…”