title: PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor.
abstract: A series of mono-morpholino 1,3,5-triazine derivatives (8a-8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.
authors.affiliation: Chemical Sciences, PGRD, Pfizer Inc, Legacy Wyeth Research, 401 N. Middletown Rd, Pearl River, NY 10965, USA. venkata699@gmail.com
authors.forename: Aranapakam M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Zecheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Osvaldo
authors.initials: O
authors.lastname: dos Santos
authors.forename: Christoph
authors.initials: C
authors.lastname: Dehnhardt
authors.forename: Efren Delos
authors.initials: ED
authors.lastname: Santos
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Robert
authors.initials: R
authors.lastname: Mallon
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
authors.forename: Larry
authors.initials: L
authors.lastname: Feldberg
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
authors.forename: Inder
authors.initials: I
authors.lastname: Chaudhary
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
mesh_terms: D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D014326:Tropanes / Q000737:chemistry; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014227:Triazines; D014326:Tropanes; D014508:Urea; C549124:1-(4-(4-(3-oxa-8-azabicyclo(3.2.1)octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases