Design, synthesis, and structure–activity-relationship of tetrahydrothiazolopyridine derivatives as potent smoothened antagonists

• A novel series of SMO antagonists were developed by a scaffold hopping strategy.
• Many compounds exhibited improved biological activities compared to Vismodegib.
• Compound 30 showed improved physical–chemical properties compared to Vismodegib.
• Compound 30 demonstrated good PK profiles with a 77% oral bioavailability.

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.

A novel series of smoothened antagonists were developed by a scaffold hopping strategy. Compounds from this new template demonstrated improved biological activities and physical–chemical properties compared with those of Vismodegib.Figure optionsDownload as PowerPoint slide