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Discovery of novel N-1 substituted pyrazolopyrimidinones as potent, selective PDE2 inhibitors.
Morriello, Gregori J; Dwyer, Michael P; Chen, Yili; Ginetti, Anthony T; Xu, Shimin; Lu, Jun; Abeywickrema, Pravien; Wang, Deping; Crespo, Alejandro; Cabalu, Tamara D; Wilson, Jonathan E; Stachel, Shawn J; Paone, Daniel V; Sinz, Christopher.
Affiliation
  • Morriello GJ; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA. Electronic address: greg_morriello@merck.com.
  • Dwyer MP; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA.
  • Chen Y; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA.
  • Ginetti AT; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA.
  • Xu S; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA.
  • Lu J; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Abeywickrema P; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Wang D; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Crespo A; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Cabalu TD; Drug Metabolism, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Wilson JE; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Stachel SJ; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Paone DV; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Sinz C; Discovery Chemistry, Merck & Co., Inc., 213 E. Grand Avenue, South San Fransisco, CA 94080, USA.
Bioorg Med Chem Lett ; 44: 128082, 2021 07 15.
Article in En | MEDLINE | ID: mdl-33991626
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phosphodiesterase Inhibitors / Pyrazoles / Pyrimidinones / Cyclic Nucleotide Phosphodiesterases, Type 2 / Drug Discovery Limits: Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2021 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phosphodiesterase Inhibitors / Pyrazoles / Pyrimidinones / Cyclic Nucleotide Phosphodiesterases, Type 2 / Drug Discovery Limits: Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2021 Document type: Article