Applications of parallel synthetic lead hopping and pharmacophore-based virtual screening in the discovery of efficient glycine receptor potentiators

Nagasree Chakka; Kristin L Andrews; Loren M Berry; Howard Bregman; Hakan Gunaydin; Liyue Huang; Angel Guzman-Perez; Matthew H Plant; Jeffrey R Simard; Jacinthe Gingras; Erin F DiMauro

doi:10.1016/j.ejmech.2017.05.036

Applications of parallel synthetic lead hopping and pharmacophore-based virtual screening in the discovery of efficient glycine receptor potentiators

Eur J Med Chem. 2017 Sep 8:137:63-75. doi: 10.1016/j.ejmech.2017.05.036. Epub 2017 May 12.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
² Department of Molecular Engineering, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
³ Department of Pharmacokinetics, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
⁴ Department of Discovery Attribute Sciences, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
⁵ Department of Neuroscience, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
⁶ Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA. Electronic address: erin.dimauro@merck.com.

PMID: 28575722
DOI: 10.1016/j.ejmech.2017.05.036

Abstract

Glycine receptors (GlyRs) are pentameric glycine-gated chloride ion channels that are enriched in the brainstem and spinal cord where they have been demonstrated to play a role in central nervous system (CNS) inhibition. Herein we describe two novel classes of glycine receptor potentiators that have been developed using similarity- and property-guided scaffold hopping enabled by parallel synthesis and pharmacophore-based virtual screening strategies. This effort resulted in the identification of novel, efficient and modular leads having favorable in vitro ADME profiles and high CNS multi-parameter optimization (MPO) scores, exemplified by azetidine sulfonamide 19 and aminothiazole sulfone (ent2)-20.

Keywords: Allosteric potentiator; Glycine receptor; Pain; Parallel synthesis; Pharmacophore-based virtual screen.

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Drug Evaluation, Preclinical
Humans
Molecular Docking Simulation
Molecular Structure
Receptors, Glycine / antagonists & inhibitors*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Receptors, Glycine
Sulfonamides