title: Pyrimidoaminotropanes as potent, selective, and efficacious small molecule kinase inhibitors of the mammalian target of rapamycin (mTOR).
abstract: We have 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 new series of small molecule inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly observed with the THQ scaffold, maintain or improve aqueous solubility and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of 20 (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor.
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc, 1 DNA Way, South San Francisco, California 94080, United States. estrada.anthony@gene.com
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Estrada
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Shore
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Dipasquale
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Epler
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Michael F T
authors.initials: MF
authors.lastname: Koehler
authors.forename: Lichuan
authors.initials: L
authors.lastname: Liu
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.forename: Frederic
authors.initials: F
authors.lastname: St-Jean
authors.forename: Lan
authors.initials: L
authors.lastname: Trinh
authors.forename: Tom
authors.initials: T
authors.lastname: Truong
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
mesh_terms: D002853:Chromatography, Liquid; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014326:Tropanes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014326:Tropanes; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases