Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): Optimization of the 1-substituent

• Published in: Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (4), p.1440-1444
• Main Authors: Curran, Kevin J., Verheijen, Jeroen C., Kaplan, Joshua, Richard, David J., Toral-Barza, Lourdes, Hollander, Irwin, Lucas, Judy, Ayral-Kaloustian, Semiramis, Yu, Ker, Zask, Arie
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Administration, Oral; Animals; Antineoplastic agents; Binding, Competitive; Biological and medical sciences; Drug Stability; General aspects; Humans; Inhibitory Concentration 50; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - metabolism; Kinase; Medical sciences; Mice; Microsomes - enzymology; Molecular Structure; mTOR; P13K; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - metabolism; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyridines - chemical synthesis; Pyridines - chemistry; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.12.086

Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon of the pyrazolopyrimidine resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8 h following oral administration and showed excellent activity in a tumor xenograft model. A series of pyrazolopyrimidine mammalian Target Of Rapamycin (mTOR) inhibitors with various substituents at the 1-position have been prepared, resulting in compounds with excellent potency, selectivity and microsomal stability. Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8 h following iv administration and showed excellent oral activity in a xenograft tumor model.