title: 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.
authors.affiliation: IRBM, Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia, 00040 Rome, Italy.
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Ontoria
authors.forename: Laura Llauger
authors.initials: LL
authors.lastname: Bufi
authors.forename: Caterina
authors.initials: C
authors.lastname: Torrisi
authors.forename: Alberto
authors.initials: A
authors.lastname: Bresciani
authors.forename: Claudia
authors.initials: C
authors.lastname: Giomini
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Sergio
authors.initials: S
authors.lastname: Serafini
authors.forename: Hu
authors.initials: H
authors.lastname: Bin
authors.forename: Wu
authors.initials: W
authors.lastname: Hao
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D053823:Hedgehog Proteins; D014508:Urea