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Identification of a series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as potent smoothened antagonist hedgehog pathway inhibitors.

Abstract：

:The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Ontoria JM,Bufi LL,Torrisi C,Bresciani A,Giomini C,Rowley M,Serafini S,Bin H,Hao W,Steinkühler C,Jones P

doi

10.1016/j.bmcl.2011.07.031

subject

Has Abstract

pub_date

2011-09-15 00:00:00

pages

5274-82

issue

18

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(11)00969-3

journal_volume

21

pub_type

杂志文章

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