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Synthesis and evaluation of a new series of 1′-cyclobutyl-6-(4-piperidyloxy)spiro[benzopyran-2,4′-piperidine] derivatives as high affinity and selective histamine-3 receptor (H3R) antagonists
- Source :
- Bioorganic & Medicinal Chemistry Letters. 22:2151-2153
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- A novel class of 1'-cyclobutyl-6-(4-piperidyloxy)spiro[benzopyran-2,4'-piperidine] derivatives with low nanomolar affinity for the human and rat histamine-3 receptors (H(3)Rs) are described. The spirobenzopyran piperidine ether analogs demonstrated excellent H(3)R affinity and selectivity against histamine receptor subtypes (H(1)R, H(2)R, and H(4)R), were stable in liver microsomes, and had selectivity against CYP P450 enzymes. Compounds 10, 13, 15, and 16 demonstrated high H(3)R affinity, in vitro liver microsomal stability, selectivity against CYP isoforms, moreover, these ether analogs exhibited acceptable iv pharmacokinetic (PK) properties but had poor oral exposure in rat.
- Subjects :
- Stereochemistry
Clinical Biochemistry
Histamine Antagonists
Administration, Oral
Pharmaceutical Science
Ether
Biochemistry
Structure-Activity Relationship
Histamine receptor
chemistry.chemical_compound
Cytochrome P-450 Enzyme System
Piperidines
Drug Discovery
Animals
Humans
Receptors, Histamine H3
Benzopyrans
Spiro Compounds
Receptor
Molecular Biology
Organic Chemistry
Rats
Benzopyran
chemistry
Injections, Intravenous
Microsomes, Liver
Microsome
Molecular Medicine
Piperidine
Selectivity
Histamine
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....928134c9c6368b1ec459a58b4cb5bded