Discovery of novel N-1 substituted pyrazolopyrimidinones as potent, selective PDE2 inhibitors

Gregori J Morriello; Michael P Dwyer; Yili Chen; Anthony T Ginetti; Shimin Xu; Jun Lu; Pravien Abeywickrema; Deping Wang; Alejandro Crespo; Tamara D Cabalu; Jonathan E Wilson; Shawn J Stachel; Daniel V Paone; Christopher Sinz

doi:10.1016/j.bmcl.2021.128082

Discovery of novel N-1 substituted pyrazolopyrimidinones as potent, selective PDE2 inhibitors

Bioorg Med Chem Lett. 2021 Jul 15:44:128082. doi: 10.1016/j.bmcl.2021.128082. Epub 2021 May 13.

Affiliations

¹ Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA. Electronic address: greg_morriello@merck.com.
² Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA.
³ Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
⁴ Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
⁵ Discovery Chemistry, Merck & Co., Inc., 213 E. Grand Avenue, South San Fransisco, CA 94080, USA.

PMID: 33991626
DOI: 10.1016/j.bmcl.2021.128082

Abstract

A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal compounds with excellent potency and selectivity. The series was derived from previously identified internal leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound 26 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.

Keywords: PDE2; Pyrazolopyrimidinone; cAMP; cGMP.

MeSH terms

Crystallography, X-Ray
Cyclic Nucleotide Phosphodiesterases, Type 2 / antagonists & inhibitors*
Cyclic Nucleotide Phosphodiesterases, Type 2 / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Models, Molecular
Molecular Structure
Phosphodiesterase Inhibitors / chemical synthesis
Phosphodiesterase Inhibitors / chemistry
Phosphodiesterase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology*
Structure-Activity Relationship

Substances

Phosphodiesterase Inhibitors
Pyrazoles
Pyrimidinones
pyrazole
Cyclic Nucleotide Phosphodiesterases, Type 2
PDE2A protein, human