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 molecu...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-10, Vol.20 (19), p.5869-5873
Hauptverfasser:	Venkatesan, Aranapakam M., Chen, Zecheng, Santos, Osvaldo Dos, Dehnhardt, Christoph, Santos, Efren Delos, Ayral-Kaloustian, Semiramis, Mallon, Robert, Hollander, Irwin, Feldberg, Larry, Lucas, Judy, Yu, Ker, Chaudhary, Inder, Mansour, Tarek S.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Antineoplastic agents Biological and medical sciences Cell Line, Tumor Dual PI3-kinase/mTOR inhibitors General aspects Humans Medical sciences Mice Mice, Nude Morpholines - chemical synthesis Morpholines - chemistry Morpholines - pharmacokinetics Pharmacology. Drug treatments Phosphatidylinositol 3-Kinase - antagonists & inhibitors Phosphatidylinositol 3-Kinase - metabolism Phosphatidylinositol-3-kinase (PI3K) PI3K/Akt/mTOR pathway PKI-179 PKI-587 Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Structure-Activity Relationship TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - metabolism Triazines - chemical synthesis Triazines - chemistry Triazines - pharmacokinetics Tropanes - chemistry Urea - analogs & derivatives Urea - chemical synthesis Urea - chemistry Urea - pharmacokinetics Xenograft Model Antitumor Assays
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.07.104