Design, synthesis, and structure-activity-relationship of phenyl imidazoles as potent Smoothened antagonists.

Cheng, Dai; Han, Dong; Gao, Wenqi; Jing, Qihui; Jiang, Jiqing; Wan, Yongqin; Englund, Nathan P; Tuntland, Tove; Wu, Xu; Pan, Shifeng

Cheng, Dai; Han, Dong; Gao, Wenqi; Jing, Qihui; Jiang, Jiqing; Wan, Yongqin; Englund, Nathan P; Tuntland, Tove; Wu, Xu; Pan, Shifeng.

Affiliation

Cheng D; Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.

Bioorg Med Chem Lett ; 22(21): 6573-6, 2012 Nov 01.

Article in En | MEDLINE | ID: mdl-23036954

ABSTRACT

ABSTRACT

Through scaffold morphing of a known Smoothened antagonist Antag691, a series of novel phenyl imidazole derivatives were developed. Structure-activity-relationship studies and lead optimization led to the discovery of potent, selective and orally bioavailable Smoothened antagonist 19 that is suitable for in vivo studies.

Subject(s)

Drug Design; Imidazoles/chemical synthesis; Imidazoles/pharmacokinetics; Receptors, G-Protein-Coupled/antagonists & inhibitors; Administration, Oral; Animals; Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/chemistry; Antineoplastic Agents/pharmacokinetics; Antineoplastic Agents/pharmacology; Area Under Curve; Humans; Imidazoles/chemistry; Imidazoles/pharmacology; Inhibitory Concentration 50; Mice; Protein Binding/drug effects; Rats; Smoothened Receptor; Structure-Activity Relationship

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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Design / Receptors, G-Protein-Coupled / Imidazoles Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2012 Type: Article Affiliation country: United States

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