1. Identification and optimisation of 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole and 4,5-dihydrothiazolo[4,5-h]quinazoline series of selective phosphatidylinositol-3 kinase alpha inhibitors.
- Author
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Fairhurst RA, Gerspacher M, Imbach-Weese P, Mah R, Caravatti G, Furet P, Fritsch C, Schnell C, Blanz J, Blasco F, Desrayaud S, Guthy DA, Knapp M, Arz D, Wirth J, Roehn-Carnemolla E, and Luu VH
- Subjects
- Animals, Caco-2 Cells, Class I Phosphatidylinositol 3-Kinases, Female, Humans, Mice, Nude, Models, Molecular, Neoplasms drug therapy, Neoplasms enzymology, Phosphatidylinositol 3-Kinases chemistry, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors therapeutic use, Quinazolines pharmacokinetics, Quinazolines therapeutic use, Structure-Activity Relationship, Thiazoles pharmacokinetics, Thiazoles therapeutic use, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Quinazolines chemistry, Quinazolines pharmacology, Thiazoles chemistry, Thiazoles pharmacology
- Abstract
A cyclisation within a 4',5-bisthiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors led to a novel 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole tricyclic sub-series. The synthesis and optimisation of this 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole sub-series and the expansion to a related tricyclic 4,5-dihydrothiazolo[4,5-h]quinazoline sub-series are described. From this work analogues including 11, 12, 19 and 23 were identified as potent and selective PI3Kα inhibitor in vivo tool compounds., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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