Discovery of dual positive allosteric modulators (PAMs) of the metabotropic glutamate 2 receptor and CysLT1 antagonists for treating migraine headache

Autor:	Fredrik Pehr Marmsater, Jeffrey M. Schkeryantz, Dana Rae Benesh, Maria-Jesus Blanco, Amy Clemens-Smith, Renee Emkey, Kirk W. Johnson, Michael P. Johnson, Fese Mokube, Groendyke Todd Michael, James Allen Knobelsdorf, Tony Pisal Tang, Mark A. Muhlhauser, Cortez Guillermo S, Thomas Daniel Aicher, Albert Khilevich, Steven Swanson, John T. Catlow
Rok vydání:	2016
Předmět:	0301 basic medicine Migraine Disorders Clinical Biochemistry Allosteric regulation Pharmaceutical Science Pharmacology Receptors Metabotropic Glutamate Biochemistry 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Dogs Allosteric Regulation Drug Discovery Animals Humans Molecular Biology Receptors Leukotriene Sulfonamides Dose-Response Relationship Drug Molecular Structure Chemistry Metabotropic glutamate receptor 5 Organic Chemistry Potentiator Rats Cysteinyl leukotriene receptor 1 030104 developmental biology Metabotropic receptor Metabotropic glutamate receptor Molecular Medicine Metabotropic glutamate receptor 1 Metabotropic glutamate receptor 2 030217 neurology & neurosurgery
Zdroj:	Bioorganicmedicinal chemistry letters. 27(2)
ISSN:	1464-3405
Popis:	Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2 receptor. The hydroxyacetophenone scaffold is a second series of mGlu2 PAMs we have identified. This series of molecules are potent mGlu2 potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::df5d8e11f4b6d50d127416a2d5c6aa8c https://pubmed.ncbi.nlm.nih.gov/27908761 Zobrazit plný text záznamu Full Text from ScienceDirect