6-Aryl-3-pyrrolidinylpyridines as mGlu5 receptor negative allosteric modulators

A series of 6-aryl-3-pyrrolidinylpyridine analogs was explored as structurally novel negative allosteric modulators of the mGlu5 receptor lacking an alkyne or oxadiazole moiety. Compounds in this series were characterized by tractable SAR, good in vitro potencies and brain penetration in rodents. A...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 21; no. 16; pp. 4891 - 4899
Main Authors:	Weiss, Jesse M., Jimenez, Hermogenes N., Li, Guiying, April, Myriam, Uberti, Michelle A., Bacolod, Maria D., Brodbeck, Robb M., Doller, Darío
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 15-08-2011 Elsevier
Subjects:	Animals Biological and medical sciences brain chemistry CNS drug discovery Dose-Response Relationship, Drug Glutamatergic system (aspartate and other excitatory aminoacids) GPCR HEK293 Cells Humans Medical sciences Metabotropic glutamate receptors mGlu5 NAM mGluR Models, Molecular Molecular Structure Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Pyrrolidines - chemical synthesis Pyrrolidines - chemistry Pyrrolidines - pharmacology Rats Rats, Sprague-Dawley Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate - antagonists & inhibitors Receptors, Metabotropic Glutamate - blood rodents Stereoisomerism Structure-Activity Relationship Metabotropic glutamate receptors GPCR CNS drug discovery mGlu5 NAM mGluR Five membered ring Group I mglu glutamate receptor Rat Nitrogen heterocycle Ligand Blood brain barrier Pyrrolidine derivatives Pyridine derivatives Structure activity relation G protein coupled receptor Chlorine Organic compounds Water solubility Chemical synthesis Sulfur nitrogen heterocycle mglu5 glutamate receptor Rodentia Oral administration In vitro In vivo Vertebrata Biological fixation Mammalia Metabotropic receptor Allosteric regulation Animal Affinity Carboxamide Property structure relationship Pharmacokinetics Lipophilicity Physicochemical properties
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Summary:	A series of 6-aryl-3-pyrrolidinylpyridine analogs was explored as structurally novel negative allosteric modulators of the mGlu5 receptor lacking an alkyne or oxadiazole moiety. Compounds in this series were characterized by tractable SAR, good in vitro potencies and brain penetration in rodents. A series of 6-aryl-3-pyrrolidinylpyridine analogs was explored as structurally novel negative allosteric modulators of the mGlu5 receptor lacking an alkyne or oxadiazole moiety. Compounds in this series were characterized by tractable SAR, good in vitro potencies and brain penetration in rodents.
Bibliography:	http://dx.doi.org/10.1016/j.bmcl.2011.06.014 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.06.014