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Benzimidazole- and indole-substituted 1,3'-bipyrrolidine benzamides as histamine H(3) receptor antagonists.

Bioorganic & medicinal chemistry letters 2009 Dec 4; In press

Link to PubMed abstract

Cole D DC, Gross J JL, Comery T TA, Aschmies S, Hirst W WD, Kelley C, Kim J JI, Kubek K, Ning X, Platt B BJ, Robichaud A AJ, Solvibile W WR, Stock J JR, Tawa G, Williams M MJ, Ellingboe J JW

Chemical Sciences, Wyeth Research, 401 N. Middletown Rd. Pearl River, NY 10965, United States.

Using a focused screen of biogenic amine compounds we identified a novel series of H(3)R antagonists. A preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimization of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and efficacy in both water intake and novel object recognition models.

Keywords: histamine object recognition H3 cognition