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Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.
Zhang, Xianglei; Dong, Guangyu; Li, Heng; Chen, Wuyan; Li, Jian; Feng, Chunlan; Gu, Zhanni; Zhu, Fenghua; Zhang, Rui; Li, Minjun; Tang, Wei; Liu, Hong; Xu, Yechun.
Afiliación
  • Zhang X; CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Drug Discovery and Design Center, Laboratory of Immunopharmacology , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • Dong G; University of Chinese Academy of Sciences , Beijing 100049 , China.
  • Li H; University of Chinese Academy of Sciences , Beijing 100049 , China.
  • Chen W; School of Life Science and Technology , ShanghaiTech University , Shanghai 201210 , China.
  • Li J; CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Drug Discovery and Design Center, Laboratory of Immunopharmacology , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • Feng C; University of Chinese Academy of Sciences , Beijing 100049 , China.
  • Gu Z; CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Drug Discovery and Design Center, Laboratory of Immunopharmacology , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • Zhu F; CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Drug Discovery and Design Center, Laboratory of Immunopharmacology , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • Zhang R; CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Drug Discovery and Design Center, Laboratory of Immunopharmacology , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • Li M; CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Drug Discovery and Design Center, Laboratory of Immunopharmacology , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • Tang W; CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Drug Discovery and Design Center, Laboratory of Immunopharmacology , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • Liu H; CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Drug Discovery and Design Center, Laboratory of Immunopharmacology , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • Xu Y; University of Chinese Academy of Sciences , Beijing 100049 , China.
J Med Chem ; 62(11): 5579-5593, 2019 06 13.
Article en En | MEDLINE | ID: mdl-31099559
Psoriasis is a common, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure-activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well-characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Psoriasis / Diseño de Fármacos / Tetrahidroisoquinolinas / Inhibidores de Fosfodiesterasa 4 Tipo de estudio: Diagnostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Psoriasis / Diseño de Fármacos / Tetrahidroisoquinolinas / Inhibidores de Fosfodiesterasa 4 Tipo de estudio: Diagnostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos