Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with improved pharmaceutical characteristics

The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorab...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2008-12, Vol.18 (23), p.6151-6155
Hauptverfasser:	PONTILLO, Joseph, DONGPEI WU, HUA WANG, WEN, Jenny, WADE, Warren S, CHINGA, Brett, HUDSON, Sarah, GENICOTA, Marc J, YINGHONG GAO, EWING, Todd, FLECK, Beth A, GOGAS, Kathleen, APARICIO, Anna
Format:	Artikel
Sprache:	eng
Schlagworte:	Atomoxetine Hydrochloride Biological and medical sciences Catecholaminergic system Combinatorial Chemistry Techniques Cytochrome P-450 CYP2D6 Inhibitors Drug Design Humans Indans - chemical synthesis Indans - chemistry Indans - pharmacology Inhibitory Concentration 50 Medical sciences Microsomes, Liver - metabolism Molecular Structure Neuropharmacology Neurotransmitter Uptake Inhibitors - chemical synthesis Neurotransmitter Uptake Inhibitors - chemistry Neurotransmitter Uptake Inhibitors - pharmacology Neurotransmitters. Neurotransmission. Receptors Norepinephrine - antagonists & inhibitors Pharmacology. Drug treatments Propylamines - pharmacology Stereoisomerism Structure-Activity Relationship
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Zusammenfassung:	The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2008.10.013