title: Design, synthesis, and structure--activity-relationship of tetrahydrothiazolopyridine derivatives as potent smoothened antagonists.
abstract: The Smoothened (Smo) receptor is an important component of the hedgehog (Hh) signaling pathway, which plays a critical role during embryonic development. In adults, Hh signaling is curtailed and has limited functions such as stem cell maintenance and tissue repair. However, aberrant activity of the Hh signaling in adults has been linked to numerous human cancers. Inhibition of Smo leads to the blockade of Hh signaling, and therefore represents a promising approach toward novel anticancer therapy. Through scaffold morphing of a few known Smo antagonists, a series of novel tetrahydrothiazolopyridine derivatives were developed. Compounds from this new scaffold demonstrated excellent Hh signaling inhibition which was comparable to or better than that of Vismodegib. Further, compound 30 exhibited a lower melting point and a moderately improved solubility compared with those of Vismodegib; compounds 11 and 30 showed good pharmacokinetic profiles with 34% and 77% oral bioavailability in rat, respectively. Collectively, these results strongly support further optimization of this novel scaffold to develop better Smo antagonists.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Haikuo
authors.initials: H
authors.lastname: Ma
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Lu
authors.affiliation: BeiGene (Beijing) Co., Ltd., No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Sun
authors.affiliation: BeiGene (Beijing) Co., Ltd., No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China. Electronic address: lusong.luo@beigene.com.
authors.forename: Lusong
authors.initials: L
authors.lastname: Luo
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Delong
authors.initials: D
authors.lastname: Geng
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Enqin
authors.initials: E
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Jiyue
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Shilin
authors.initials: S
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China. Electronic address: xiaohuzhang@suda.edu.cn.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D012995:Solubility; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000600802:1-(5-(5'-chloro-3,5-dimethyl-(2,4'-bipyridin)-2'-yl)-4,5,6,7-tetrahydrothiazolo(5,4-c)pyridin-2-yl)piperidin-4-ol; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D013844:Thiazoles
keywords: Antagonist; Cancer therapy; GPCR; Hedgehog signaling pathway; Scaffold hopping; Smoothened