Discovery and optimization of a novel CNS penetrant series of mGlu4 PAMs based on a 1,4-thiazepane core with in vivo efficacy in a preclinical Parkinsonian model

Caitlin N Kent; Mark G Fulton; Kaylee J Stillwell; Jonathan W Dickerson; Matthew T Loch; Alice L Rodriguez; Anna L Blobaum; Olivier Boutaud; Jerri L Rook; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley

doi:10.1016/j.bmcl.2021.127838

Discovery and optimization of a novel CNS penetrant series of mGlu₄ PAMs based on a 1,4-thiazepane core with in vivo efficacy in a preclinical Parkinsonian model

Bioorg Med Chem Lett. 2021 Apr 1:37:127838. doi: 10.1016/j.bmcl.2021.127838. Epub 2021 Feb 5.

Affiliations

¹ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
² Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
³ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].

PMID: 33556572
DOI: 10.1016/j.bmcl.2021.127838

Abstract

A high throughput screen (HTS) identified a novel, but weak (EC₅₀ = 6.2 μM, 97% Glu Max) mGlu₄ PAM chemotype based on a 1,4-thiazepane core, VU0544412. Reaction development and chemical optimization delivered a potent mGlu₄ PAM VU6022296 (EC₅₀ = 32.8 nM, 108% Glu Max) with good CNS penetration (K_p = 0.45, K_p,uu = 0.70) and enantiopreference. Finally, VU6022296 displayed robust, dose-dependent efficacy in reversing Haloperidol-Induced Catalepsy (HIC), a rodent preclinical Parkinson's disease model.

Keywords: Metabotropic glutamate receptor; Positive allosteric modulator (PAM); Structure-activity-relationship (SAR); mGlu(4).

MeSH terms

Allosteric Regulation / drug effects
Animals
Catalepsy / chemically induced
Catalepsy / drug therapy*
Disease Models, Animal*
Dose-Response Relationship, Drug
Drug Discovery*
Haloperidol
Mice
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Parkinson Disease / drug therapy*
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Receptors, Metabotropic Glutamate / metabolism
Structure-Activity Relationship

Substances

Neuroprotective Agents
Receptors, Metabotropic Glutamate
Haloperidol