ABSTRACT
The discovery and optimization of a series of imidazo[1,5-a]pyrazine inhibitors of mTOR is described. HTS hits were optimized for potency, selectivity and metabolic stability to provide the orally bioavailable proof of concept compound 4c that demonstrated target inhibition in vivo and concomitant inhibition of tumor growth in an MDA-MB-231 xenograft model.
Subject(s)
Imidazoles/pharmacology , Proteins/antagonists & inhibitors , Pyrazines/pharmacology , Transcription Factors/antagonists & inhibitors , Administration, Oral , Cell Line, Tumor , Humans , Imidazoles/administration & dosage , Mechanistic Target of Rapamycin Complex 1 , Models, Molecular , Multiprotein Complexes , Pyrazines/administration & dosage , TOR Serine-Threonine Kinases , Xenograft Model Antitumor AssaysABSTRACT
A highly effective one-pot Friedländer quinoline synthesis using inexpensive reagents has been developed. o-Nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of catalytic HCl (aq.) and subsequently condensed in situ with aldehydes or ketones to form mono- or di-substituted quinolines in high yields (66-100%).
Subject(s)
Aldehydes/chemistry , Benzaldehydes/chemistry , Quinolines/chemical synthesis , Iron/chemistry , Ketones/chemistry , Molecular Structure , Oxidation-Reduction , Quinolines/chemistryABSTRACT
A series of novel 8-amino-1,3-disubstituted-imidazo[1,5-a]pyrazines was designed and synthesized as IGF-IR inhibitors.
