title: Parallel synthesis of diarylureas and their evaluation as inhibitors of insulin-like growth factor receptor.
abstract: Diarylurea (DAU) compounds, particularly species composed of a heteroaryl ring system conjugated through a urea linkage to a substituted arene, were previously identified by the screening of a diverse chemical library to be active against the insulin growth factor receptor (IGF-1R). DAU compounds 4{a,b} were synthesized in parallel by the coupling of aryl amines 2{a} with aryl isocyanates 3{b}. Preparative RP-HPLC purification was found necessary to remove an impurity 5{b}, the symmetric urea resulting from the hydrolytic degradation of aryl isocyanates. Two libraries of DAU compounds were prepared to perform preliminary optimization of the two-ring systems for inhibitory activity against IGF-1R. In the first library, we explored a series of heteroaryl ring systems and found the 4-aminoquinaldine ring system to be optimal among those evaluated. The second library fixed the 4-aminoquinaldine ring system and we evaluated a series of substituted arenes conjugated to it. Overall, eight compounds based on the 4-aminoquinaldine heteroaryl system were found to have moderate activity against IGF-1R with IC(50) values better than 40 microM.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, Box 2280, San Francisco, California 94143-2280, USA.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Anderson
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Cristina
authors.initials: C
authors.lastname: Penaranda
authors.forename: Betty A
authors.initials: BA
authors.lastname: Maddux
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
authors.forename: Jack F
authors.initials: JF
authors.lastname: Youngren
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000818:Animals; D016466:CHO Cells; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D014508:Urea / Q000737:chemistry*
chemical_list: D047428:Protein Kinase Inhibitors; D014508:Urea; D017526:Receptor, IGF Type 1