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

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.

Afiliación

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 en En | MEDLINE | ID: mdl-33991626

ABSTRACT

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.

Asunto(s)

Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores; Descubrimiento de Drogas; Inhibidores de Fosfodiesterasa/farmacología; Pirazoles/farmacología; Pirimidinonas/farmacología; Cristalografía por Rayos X; Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo; Relación Dosis-Respuesta a Droga; Humanos; Modelos Moleculares; Estructura Molecular; Inhibidores de Fosfodiesterasa/síntesis química; Inhibidores de Fosfodiesterasa/química; Pirazoles/síntesis química; Pirazoles/química; Pirimidinonas/síntesis química; Pirimidinonas/química; Relación Estructura-Actividad

Palabras clave

PDE2; Pyrazolopyrimidinone; cAMP; cGMP

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Fosfodiesterasa / Pirazoles / Pirimidinonas / Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2 / Descubrimiento de Drogas Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2021 Tipo del documento: Article Pais de publicación: ENGLAND / ESCOCIA / GB / GREAT BRITAIN / INGLATERRA / REINO UNIDO / SCOTLAND / UK / UNITED KINGDOM

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