Benzothiophene derivatives as phosphodiesterase 10A (PDE10A) inhibitors: Hit-to-lead studies.

Kawamoto, Yoshito; Tomino, Minako; Hiramatsu, Kenichi; Oyama, Yoshiaki; Hayashi, Yasuhiro

Kawamoto, Yoshito; Tomino, Minako; Hiramatsu, Kenichi; Oyama, Yoshiaki; Hayashi, Yasuhiro.

Afiliación

Kawamoto Y; Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: kawamoto.yoshito.e2@daiichisankyo.co.jp.
Tomino M; Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Hiramatsu K; Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Oyama Y; Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Hayashi Y; Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.

Bioorg Med Chem Lett ; 29(11): 1419-1422, 2019 06 01.

Article en En | MEDLINE | ID: mdl-30952590

ABSTRACT

ABSTRACT

A novel series of benzothiophene derivatives was discovered as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity relationship studies on high-throughput screening hit compound 1 led to the identification of 7-acetyl-3-methyl-N-(quinolin-2-yl)-1-benzothiophene-2-carboxamide (16), with potent inhibitory activity (PDE10A IC50â¯=â¯7.6â¯nM) and selectivity (>1300-fold selectivity over the other tested phosphodiesterases). In addition, a novel methyl-induced conformational alteration of the benzothiophene-2-carboxamide derivatives is reported.

Asunto(s)

Inhibidores de Fosfodiesterasa/farmacología; Hidrolasas Diéster Fosfóricas/metabolismo; Tiofenos/farmacología; Cristalografía por Rayos X; Relación Dosis-Respuesta a Droga; Humanos; Modelos Moleculares; Estructura Molecular; Inhibidores de Fosfodiesterasa/síntesis química; Inhibidores de Fosfodiesterasa/química; Relación Estructura-Actividad; Tiofenos/síntesis química; Tiofenos/química

Palabras clave

Benzothiophene; Conformational alteration; Hit-to-lead studies; PDE10A inhibitors; Phosphodiesterase 10A inhibitors

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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Inhibidores de Fosfodiesterasa / Tiofenos / Hidrolasas Diéster Fosfóricas Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article

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