학술논문
Pyrimidoaminotropanesas Potent, Selective, and EfficaciousSmall Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin(mTOR).
Document Type
Article
Author
Estrada, Anthony A.; Shore, Daniel G.; Blackwood, Elizabeth; Chen, Yung-Hsiang; Deshmukh, Gauri; Ding, Xiao; DiPasquale, AntonioG.; Epler, Jennifer A.; Friedman, Lori S.; Koehler, Michael F. T.; Liu, Lichuan; Malek, Shiva; Nonomiya, Jim; Ortwine, DanielF.; Pei, Zhonghua; Sideris, Steve; St-Jean, Frederic; Trinh, Lan; Truong, Tom; Lyssikatos, JosephP.
Source
Subject
*KINASE inhibitors
*AMINO group
*RAPAMYCIN
*TARGETED drug delivery
*MAMMAL diseases
*PHARMACEUTICAL chemistry
*THERAPEUTICS
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Language
ISSN
0022-2623
Abstract
Wehave recently reported a series of tetrahydroquinazoline (THQ)mTOR inhibitors that produced a clinical candidate 1(GDC-0349).Through insightful design, we hoped to discover and synthesize a newseries of small molecule inhibitors that could attenuate CYP3A4 time-dependentinhibition commonly observed with the THQ scaffold, maintain or improveaqueous solubility and oral absorption, reduce free drug clearance,and selectively increase mTOR potency. Through key in vitro and invivo studies, we demonstrate that a pyrimidoaminotropane based corewas able to address each of these goals. This effort culminated inthe discovery of 20(GNE-555), a highly potent, selective,metabolically stable, and efficacious mTOR inhibitor. [ABSTRACT FROM AUTHOR]