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

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

doi:10.1016/j.bmcl.2012.09.013

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

Bioorg Med Chem Lett. 2012 Nov 1;22(21):6573-6. doi: 10.1016/j.bmcl.2012.09.013. Epub 2012 Sep 13.

Authors

Dai Cheng¹, Dong Han, Wenqi Gao, Qihui Jing, Jiqing Jiang, Yongqin Wan, Nathan P Englund, Tove Tuntland, Xu Wu, Shifeng Pan

Affiliation

¹ Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.

PMID: 23036954
DOI: 10.1016/j.bmcl.2012.09.013

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.

MeSH terms

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

Substances

Antineoplastic Agents
Imidazoles
Receptors, G-Protein-Coupled
SMO protein, human
Smoothened Receptor
imidazole