Journal article
Synthesis and evaluation of pyridone-phenoxypropyl-R-2-methylpyrrolidine analogues as histamine H-3 receptor antagonists
Bioorganic & medicinal chemistry letters, v 21(23), pp 7076-7080
01 Dec 2011
PMID: 22014551
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
6-{4-[3-(R)-2-Methylpyrrolidin-1-yl) propoxy]-phenyl}-2H-pyridazin-3-one 6 (Irdabisant; CEP-26401) was recently reported as a potent H3R antagonist with excellent drug-like properties and in vivo activity that advanced into clinical evaluation. A series of pyridone analogs of 6 was synthesized and evaluated as H3R antagonists. Structure-activity relationships revealed that the 5-pyridone regiomer was optimal for H3R affinity. N-Methyl 9b showed excellent H3R affinity, acceptable pharmacokinetics and pharmaceutical properties. In vivo evaluation of 9b showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG model. (C) 2011 Elsevier Ltd. All rights reserved.
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Details
- Title
- Synthesis and evaluation of pyridone-phenoxypropyl-R-2-methylpyrrolidine analogues as histamine H-3 receptor antagonists
- Creators
- Nadine C. Becknell - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAJacquelyn A. Lyons - Cephalon Inc, Discovery Res, W Chester, PA 19380 USALisa D. Aimone - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAJohn A. Gruner - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAJoanne R. Mathiasen - Cephalon Inc, Discovery Res, W Chester, PA 19380 USARita Raddatz - Cephalon Inc, Discovery Res, W Chester, PA 19380 USARobert L. Hudkins - Cephalon Inc, Discovery Res, W Chester, PA 19380 USA
- Publication Details
- Bioorganic & medicinal chemistry letters, v 21(23), pp 7076-7080
- Publisher
- Elsevier
- Number of pages
- 5
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000296717600030
- Scopus ID
- 2-s2.0-80255127310
- Other Identifier
- 991021900193604721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Chemistry, Medicinal
- Chemistry, Organic