Discovery of (1R, 6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]3,4-diaza-bicyclo[4.1.0] hept-4-en-2-one (R, S-4a): Histamine H3 receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity

Robert L. Hudkins; Kurt A. Josef; Nadine C. Becknell; Lisa D. Aimone; Jacquelyn A. Lyons; Joanne R. Mathiasen; John A. Gruner; Rita Raddatz

doi:10.1016/j.bmcl.2014.01.061

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Discovery of (1R, 6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]3,4-diaza-bicyclo[4.1.0] hept-4-en-2-one (R, S-4a): Histamine H3 receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity

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Discovery of (1R, 6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]3,4-diaza-bicyclo[4.1.0] hept-4-en-2-one (R, S-4a): Histamine H3 receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity

Robert L. Hudkins, Kurt A. Josef, Nadine C. Becknell, Lisa D. Aimone, Jacquelyn A. Lyons, Joanne R. Mathiasen, John A. Gruner and Rita Raddatz

Bioorganic & medicinal chemistry letters, v 24(5), pp 1303-1306

01 Mar 2014

DOI: https://doi.org/10.1016/j.bmcl.2014.01.061

PMID: 24513042

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Abstract

Chemistry

Chemistry, Medicinal

Chemistry, Organic

Life Sciences & Biomedicine

Pharmacology & Pharmacy

Physical Sciences

Science & Technology

A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0] hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R, 6S)-5[ 4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0] hept-4-en-2-one (R, S-4a) as a secondgeneration pyridazin-3-one H3R antagonist. Compound R, S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po. (C) 2014 Elsevier Ltd. All rights reserved.

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Title: Discovery of (1R, 6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]3,4-diaza-bicyclo[4.1.0] hept-4-en-2-one (R, S-4a): Histamine H3 receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity
Creators: Robert L. Hudkins - Teva Pharmaceuticals (United States)
Kurt A. Josef - Teva Pharmaceuticals (United States)
Nadine C. Becknell - Teva Pharmaceuticals (United States)
Lisa D. Aimone - Teva Pharmaceuticals (United States)
Jacquelyn A. Lyons - Teva Pharmaceuticals (United States)
Joanne R. Mathiasen - Teva Pharmaceuticals (United States)
John A. Gruner - Teva Pharmaceuticals (Czechia)
Rita Raddatz - Teva Pharmaceuticals (United States)
Publication Details: Bioorganic & medicinal chemistry letters, v 24(5), pp 1303-1306
Publisher: Elsevier
Number of pages: 4
Resource Type: Journal article
Language: English
Academic Unit: Pharmacology and Physiology
Web of Science ID: WOS:000331705200011
Scopus ID: 2-s2.0-84894519100
Other Identifier: 991021900191904721

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Web of Science research areas: Chemistry, Medicinal; Chemistry, Organic

Discovery of (1R, 6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]3,4-diaza-bicyclo[4.1.0] hept-4-en-2-one (R, S-4a): Histamine H3 receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity

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Abstract

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UN Sustainable Development Goals (SDGs)

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