Benzimidazole- and indole-substituted 1,3 0 -bipyrrolidine benzamides as histamine H 3 receptor antagonists Derek C. Cole a, * , Jonathan L. Gross b , Thomas A. Comery c , Suzan Aschmies c , Warren D. Hirst c , Cody Kelley c,  , Ji-In Kim b , Katie Kubek c , Xiaoping Ning c,à , Brian J. Platt c , Albert J. Robichaud b , William R. Solvibile b , Joseph R. Stock a , Gregory Tawa b , Marla J. Williams b , John W. Ellingboe a a Chemical Sciences, Wyeth Research, 401 N. Middletown Rd. Pearl River, NY 10965, United States b Chemical Sciences, Wyeth Research, Princeton, NJ 08852, United States c Neuroscience, Wyeth Research, Princeton, NJ 08852, United States article info Article history: Received 19 October 2009 Revised 20 November 2009 Accepted 24 November 2009 Available online 4 December 2009 Keywords: Histamine H3 receptor antagonist Histamine H3 receptor inverse agonist abstract 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. Optimiza- tion 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. Ó 2009 Elsevier Ltd. All rights reserved. Histamine-3 receptors (H 3 R) are one of four histamine G-pro- tein coupled receptor subtypes (H 1–4 R). 1–3 H 1 R and H 2 R are post- synaptic receptors involved with allergic responses and gastric acid secretion, respectively, while the H 4 R is located on T-cells, neutrophils and monocytes and is implicated in inflammation pro- cesses. 4,5 The H 3 R is located presynaptically on histaminergic neu- rons in the CNS, where it acts as an autoreceptor inhibiting the synthesis and release of histamine. H 3 R also acts as a heterorecep- tor on non-histaminergic neurons inhibiting the release of other neurotransmitters, including acetylcholine, serotonin, noradrena- line and dopamine. Postmortem studies in humans suggest that decreased brain histamine levels may contribute to the cognitive decline in Alzheimer’s disease. 6 Furthermore H 3 R agonists have been shown to impair memory, 7,8 while H 3 R antagonists rescue pharmacologically or genetically induced impairments in various animal models. 9–13 Based on these findings several H 3 R antagonists have advanced to clinical trials for cognitive disorders and dementia. 14 Early H 3 R antagonists maintained the histamine imidazole ring, typically connected through an alkyl chain and polar fragment, such as an ether, to a lipophilic moiety (see ciproxifan, 1 15 and FUB 181, 2 16 Fig. 1). The presence of the imidazole ring has been implicated in potential pharmacokinetic liabilities 17 and poor brain penetration, so more recent analogs have focused on imidazole ring replacements, typically with a tertiary amine, (see 3–5). 18–20 Wyeth’s H 3 R program was initiated with a screen of our focused biogenic amine library using a competitive binding assay 21 with [ 3 H](R)-a-methylhistamine and cell membranes from HEK293T 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.11.122 * Corresponding author. Tel.: +1 845 602 4619; fax: +1 845 602 5561. E-mail address: coledc@wyeth.com (D.C. Cole).   Present address: Rutgers University, Newark, NJ 08854, United States. à Present address: J&J Pharmaceutical Research & Development, Titusville, NJ 08560, United States. O O N HN 1 (ciproxifan) 3 (JNJ-5207852) O N HN 2 (FUB 181) Cl N O N O N CN 4 (ABT-239) N O N H N O 5 (GSK-189254) N N O N N 6a Figure 1. Structures of H 3 R antagonists. Bioorganic & Medicinal Chemistry Letters 20 (2010) 1237–1240 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl