4-[6-(2-Aminoethyl)naphthalen-2-yl]benzonitriles are potent histamine H3 receptor antagonists with high CNS penetration.

4-[6-(2-Tertiaryaminoethyl)naphthalen-2-yl]benzonitriles are conformationally constrained histamine H3 receptor antagonists with high potency and selectivity. The analogs were designed around a naphthalene core, with the goal of enhancing lipophilicity and CNS penetration, as compared to a previously reported benzofuran series. The SAR of the tertiary amine moiety is similar to that reported for the benzofuran series, with analogs bearing a 2-methylpyrrolidine substituent possessing the greatest rat and human H3 receptor binding affinities.

[1]  Thomas R. Miller,et al.  Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and Selective Histamine H3 Receptor Antagonist with Drug-Like Properties , 2005, Journal of Pharmacology and Experimental Therapeutics.

[2]  Min Zhang,et al.  Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H3 Receptor Antagonist , 2005, Journal of Pharmacology and Experimental Therapeutics.

[3]  E. Bush,et al.  Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor antagonist. , 2004, European journal of pharmacology.

[4]  J. Schwartz,et al.  Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor , 1983, Nature.

[5]  J. Schwartz,et al.  Influence of imidazole replacement in different structural classes of histamine H(3)-receptor antagonists. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[6]  R. Leurs,et al.  Therapeutic potential of histamine H3 receptor agonists and antagonists. , 1998, Trends in pharmacological sciences.

[7]  J. Schwartz,et al.  Histamine H3‐receptor‐mediated [35S]GTPγ[S] binding: evidence for constitutive activity of the recombinant and native rat and human H3 receptors , 2002, British journal of pharmacology.

[8]  P. Leeson,et al.  A comparison of physiochemical property profiles of development and marketed oral drugs. , 2003, Journal of medicinal chemistry.

[9]  J. Schwartz,et al.  Effects of histamine H3-receptor ligands on various biochemical indices of histaminergic neuron activity in rat brain. , 1989, European journal of pharmacology.

[10]  Sandy J. Wilson,et al.  Acute wake‐promoting actions of JNJ‐5207852, a novel, diamine‐based H3 antagonist , 2004 .

[11]  M. Mehlman.  Cognition-enhancing drugs. , 2004, The Milbank quarterly.

[12]  R. Leurs,et al.  The histamine H3 receptor: from gene cloning to H3 receptor drugs , 2005, Nature Reviews Drug Discovery.

[13]  C. Dvorak,et al.  A new class of diamine-based human histamine H3 receptor antagonists: 4-(aminoalkoxy)benzylamines. , 2003, Journal of medicinal chemistry.

[14]  S. M. Knudsen,et al.  1-alkyl-4-acylpiperazines as a new class of imidazole-free histamine H(3) receptor antagonists. , 2004, Journal of medicinal chemistry.

[15]  H. H. Refsgaard,et al.  Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight , 2005, International Journal of Obesity.

[16]  Holger Stark,et al.  High constitutive activity of native H3 receptors regulates histamine neurons in brain , 2000, Nature.

[17]  J. Hey,et al.  Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine. , 2003, Bioorganic & medicinal chemistry letters.

[18]  Michael Williams,et al.  Two Novel and Selective Nonimidazole Histamine H3 Receptor Antagonists A-304121 and A-317920: I. In Vitro Pharmacological Effects , 2003, Journal of Pharmacology and Experimental Therapeutics.

[19]  A. Vasudevan,et al.  Aminoalkoxybiphenylnitriles as histamine-3 receptor ligands. , 2002, Bioorganic & medicinal chemistry letters.

[20]  Walter A. Korfmacher,et al.  Pharmacological Characterization of the Novel Histamine H3-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687) , 2003, Journal of Pharmacology and Experimental Therapeutics.

[21]  A. Hancock,et al.  A new class of potent non-imidazole H(3) antagonists: 2-aminoethylbenzofurans. , 2004, Bioorganic & medicinal chemistry letters.

[22]  H. Haas,et al.  International Union of Pharmacology. XIII. Classification of histamine receptors. , 1997, Pharmacological reviews.

[23]  Rob Leurs,et al.  Keynote review: histamine H3 receptor antagonists reach out for the clinic. , 2005, Drug discovery today.

[24]  H. Stark,et al.  Ciproxifan and chemically related compounds are highly potent and selective histamine H3-receptor antagonists , 1998, Naunyn-Schmiedeberg's Archives of Pharmacology.

[25]  G. Fox,et al.  Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders. , 2006, Molecular interventions.

[26]  R. Pedrosa,et al.  A Simple Stereoselective Synthesis of Enantiopure 2‐Substituted Pyrrolidines and Piperidines from Chiral (R)‐Phenylglycinol‐Derived Bicyclic 1,3‐Oxazolidines , 2000 .

[27]  W. Chai,et al.  Non-imidazole heterocyclic histamine H3 receptor antagonists. , 2003, Bioorganic & medicinal chemistry letters.

[28]  J. Schwartz,et al.  Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist. , 1998, The Journal of pharmacology and experimental therapeutics.

[29]  J. Sullivan,et al.  4-(2-[2-(2(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofuran H3 receptor antagonists potently enhance cognition and attention. , 2005, Journal of medicinal chemistry.

[30]  J. Schwartz,et al.  Structural variations of 1-(4-(phenoxymethyl)benzyl)piperidines as nonimidazole histamine H3 receptor antagonists. , 2004, Bioorganic & medicinal chemistry.

[31]  Xiaohong Zhu,et al.  Identification of a novel, orally bioavailable histamine H(3) receptor antagonist based on the 4-benzyl-(1H-imidazol-4-yl) template. , 2002, Bioorganic & medicinal chemistry letters.

[32]  H. Stark.  Recent advances in histamine H3/H4 receptor ligands , 2003 .

[33]  Stephen R. Johnson,et al.  Molecular properties that influence the oral bioavailability of drug candidates. , 2002, Journal of medicinal chemistry.

[34]  M. Jackson,et al.  Cloning and functional expression of the human histamine H3 receptor. , 1999, Molecular pharmacology.