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

Maria-Jesus Blanco; Dana R Benesh; James A Knobelsdorf; Albert Khilevich; Guillermo S Cortez; Fese Mokube; Thomas D Aicher; Todd M Groendyke; Fredrik P Marmsater; Tony P Tang; Kirk W Johnson; Amy Clemens-Smith; Mark A Muhlhauser; Steven Swanson; John Catlow; Renee Emkey; Michael P Johnson; Jeffrey M Schkeryantz

doi:10.1016/j.bmcl.2016.11.049

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

Bioorg Med Chem Lett. 2017 Jan 15;27(2):323-328. doi: 10.1016/j.bmcl.2016.11.049. Epub 2016 Nov 18.

Authors

Maria-Jesus Blanco¹, Dana R Benesh², James A Knobelsdorf², Albert Khilevich², Guillermo S Cortez², Fese Mokube², Thomas D Aicher³, Todd M Groendyke³, Fredrik P Marmsater³, Tony P Tang³, Kirk W Johnson², Amy Clemens-Smith², Mark A Muhlhauser², Steven Swanson², John Catlow², Renee Emkey², Michael P Johnson², Jeffrey M Schkeryantz²

Affiliations

¹ Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: blanco_maria@lilly.com.
² Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
³ Array BioPharma Inc., Boulder, CO, USA.

PMID: 27908761
DOI: 10.1016/j.bmcl.2016.11.049

Abstract

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.

Keywords: Allosteric modulators; CysLT1; Metabotropic glutamate receptor; Migraine; PAMs; mGlu(2).

MeSH terms

Allosteric Regulation / drug effects
Animals
Dogs
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Migraine Disorders / drug therapy*
Molecular Structure
Rats
Receptors, Leukotriene / metabolism*
Receptors, Metabotropic Glutamate / agonists
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Structure-Activity Relationship
Sulfonamides / administration & dosage
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Receptors, Leukotriene
Receptors, Metabotropic Glutamate
Sulfonamides
metabotropic glutamate receptor 2
leukotriene D4 receptor