3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake-promoting activity

Robert L Hudkins; Nadine C Becknell; Jacquelyn A Lyons; Lisa D Aimone; Mark Olsen; R Curtis Haltiwanger; Joanne R Mathiasen; Rita Raddatz; John A Gruner

doi:10.1016/j.ejmech.2015.03.054

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3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake-promoting activity

Journal article

Open access

Peer reviewed

3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake-promoting activity

Robert L Hudkins, Nadine C Becknell, Jacquelyn A Lyons, Lisa D Aimone, Mark Olsen, R Curtis Haltiwanger, Joanne R Mathiasen, Rita Raddatz and John A Gruner

European journal of medicinal chemistry, v 95, pp 349-356

05 May 2015

DOI: https://doi.org/10.1016/j.ejmech.2015.03.054

PMID: 25827402

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Abstract

Animals

Dose-Response Relationship, Drug

Drug Design

Drug Inverse Agonism

Histamine Antagonists - chemistry

Histamine Antagonists - pharmacokinetics

Histamine Antagonists - pharmacology

Humans

Pyridazines - chemistry

Pyridazines - pharmacokinetics

Pyridazines - pharmacology

Pyrrolidines - chemistry

Pyrrolidines - pharmacokinetics

Pyrrolidines - pharmacology

Rats

Receptors, Histamine H3 - metabolism

Stereoisomerism

Structure-Activity Relationship

Wakefulness - drug effects

A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6. Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1R,6S)-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H3R candidate. Diastereomer 25 had high H3R binding affinity, excellent selectivity, displayed potent H3R functional antagonism and robust wake-promoting activity in vivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development.

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Title: 3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake-promoting activity
Creators: Robert L Hudkins - Teva Pharmaceuticals (United States)
Nadine C Becknell - Teva Pharmaceuticals (United States)
Jacquelyn A Lyons - Teva Pharmaceuticals (United States)
Lisa D Aimone - Teva Pharmaceuticals (United States)
Mark Olsen - Teva Pharmaceuticals (United States)
R Curtis Haltiwanger - Teva Pharmaceuticals (United States)
Joanne R Mathiasen - Teva Pharmaceuticals (United States)
Rita Raddatz - Teva Pharmaceuticals (United States)
John A Gruner - Teva Pharmaceuticals (Czechia)
Publication Details: European journal of medicinal chemistry, v 95, pp 349-356
Publisher: Elsevier
Resource Type: Journal article
Language: English
Academic Unit: Pharmacology and Physiology
Web of Science ID: WOS:000354139900029
Scopus ID: 2-s2.0-84925773552
Other Identifier: 991021900195304721

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Web of Science research areas: Chemistry, Medicinal

3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake-promoting activity

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UN Sustainable Development Goals (SDGs)

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