Synthesis and SAR of novel histamine H3 receptor antagonists

Jesudason, Cynthia D.; Beavers, Lisa S.; Cramer, Jeffrey W.; Dill, Joelle; Finley, Don R.; Lindsley, Craig W.; Stevens, Frits C.; Gadski, Robert A.; Oldham, Samuel W.; Pickard, Richard T.; Siedem, Christopher S.; Sindelar, Dana K.; Singh, Ajay P.; Watson, Brian M.; Hipskind, Philip A.

doi:10.1016/j.bmcl.2006.04.004

Cited by 36 publications

(11 citation statements)

References 27 publications

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“…Compound 31 has good rat pharmacokinetics (%F=>100%) and inhibits the ex-vivo binding of R--methyl histamine in rat brain following p.o. administration (IC 50 =5.3 mg/kg) indicating reasonable brain exposure for this compound [76]. Compounds structurally related to 28 and 31 include the 4-aryltetrahydroisoquinolines, represented by JNJ-28583867 (32).…”

Section: -Aminopropanols and Related Ligandsmentioning

confidence: 99%

Histamine H3 Antagonists as Wake-Promoting and Pro-Cognitive Agents

Stocking

Letavic²

2008

CTMC

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The histamine H3 receptor is a pre-synaptic auto- and hetero-receptor that controls the release of histamine and a variety of other neurotransmitters in the brain. As such, modulation of the histamine H(3) receptor is expected to affect wake via control of the release of histamine and to affect cognition via regulation of several other neurotransmitters including acetylcholine and norepinephrine. Over the last several years numerous pre-clinical studies have shown that histamine H3 antagonists promote wakefulness, improve cognition, and in some cases affect food intake. Based on the interest level generated from these early pharmacology studies, and following the cloning and expression of the human histamine H3 receptor, many pharmaceutical companies began drug discovery programs aimed at the identification of histamine H3 antagonists suitable for human clinical trials. These efforts have led to many new chemotypes, and several promising compounds have recently entered the clinic for a variety of conditions, including ADHD, Narcolepsy, EDS associated with Narcolepsy, Cognitive disorders and Schizophrenia. Recent efforts towards the identification and pharmacological characterization of novel histamine H3 antagonists will be discussed.

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Section: -Aminopropanols and Related Ligandsmentioning

confidence: 99%

Histamine H3 Antagonists as Wake-Promoting and Pro-Cognitive Agents

Stocking

Letavic²

2008

CTMC

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“…This conclusion is further reinforced by the high potency of the marine natural product Aplysamine 4 [13] and other more rigid diamines recently appearing in the literature (e.g. 2 [14] and 3 [15]). In an effort to further improve our diamine H 3 pharmacophore model, and potentially enhancing the drug-like properties of the molecules, we considered adding a conformationally restricted side-chain to replace the propyloxy group linking the NR 3 R 4 amine and the aryl ring found in 8.…”

Section: Introductionmentioning

confidence: 69%

“…5.1.1.8. 4-(4-Piperidin-1-yl-but-1-ynyl)-benzaldehyde (14). To a solution of toluene-4-sulfonic acid 4-(4-formyl-phenyl)-but-3-ynyl ester (3.62 g, 11.0 mmol) in DMF (5 mL …”

Section: Chemistrymentioning

confidence: 99%

Diamine-based human histamine H3 receptor antagonists: (4-Aminobutyn-1-yl)benzylamines

Dvorak

Apodaca

Xiao

et al. 2009

European Journal of Medicinal Chemistry

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“…Tetrahydroisoquinolinones are part of biologically important molecules and have been used as intermediates in the synthesis of various scaffolds. Grunewald et al 18 have demonstrated the use of tetrahydroisoquinolinones as substrates exhibiting PNMT inhibitory activity and these derivatives have been synthesized [19][20][21][22] in the past using strategies like Bischler-Napieralski cyclization and amide formation reactions.…”

Section: Introductionmentioning

confidence: 99%