PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor.
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.
Venkatesan
Aranapakam M
AM
Chemical Sciences, PGRD, Pfizer Inc, Legacy Wyeth Research, 401 N. Middletown Rd, Pearl River, NY 10965, USA. venkata699@gmail.com
Chen
Zecheng
Z
dos Santos
Osvaldo
O
Dehnhardt
Christoph
C
Santos
Efren Delos
ED
Ayral-Kaloustian
Semiramis
S
Mallon
Robert
R
Hollander
Irwin
I
Feldberg
Larry
L
Lucas
Judy
J
Yu
Ker
K
Chaudhary
Inder
I
Mansour
Tarek S
TS
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
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