title: 4-Substituted-7-azaindoles bearing a ureidobenzofuranone moiety as potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR).
abstract: A series of 5-ureidobenzofuranones was discovered as potent and selective inhibitors of mTOR with good cellular activity. Molecular modeling studies revealed several hydrogen bond interactions of the ureido group with the enzyme at the ATP-binding site. Furthermore, modeling showed that the ureido group is best situated at C-5 of the benzofuranone. Syntheses of 4-ureido and 5-ureidobenzofuranones are presented.
authors.affiliation: Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States. tsouh@wyeth.com
authors.forename: Hwei-Ru
authors.initials: HR
authors.lastname: Tsou
authors.forename: Gloria
authors.initials: G
authors.lastname: MacEwan
authors.forename: Gary
authors.initials: G
authors.lastname: Birnberg
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Natasja
authors.initials: N
authors.lastname: Brooijmans
authors.forename: Lourdes
authors.initials: L
authors.lastname: Toral-Barza
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D007527:Isoenzymes / Q000737:chemistry; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D020123:Sirolimus; D040681:Structural Homology, Protein; D058570:TOR Serine-Threonine Kinases
chemical_list: D000255:Adenosine Triphosphate; D001572:Benzofurans; D058544:Class Ib Phosphatidylinositol 3-Kinase; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546760:PIK3CG protein, human