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

Robin A Fairhurst; Marc Gerspacher; Patricia Imbach-Weese; Robert Mah; Giorgio Caravatti; Pascal Furet; Christine Fritsch; Christian Schnell; Joachim Blanz; Francesca Blasco; Sandrine Desrayaud; Daniel A Guthy; Mark Knapp; Dorothee Arz; Jasmin Wirth; Esther Roehn-Carnemolla; Van Huy Luu

doi:10.1016/j.bmcl.2015.06.067

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

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3575-81. doi: 10.1016/j.bmcl.2015.06.067. Epub 2015 Jun 26.

Authors

Robin A Fairhurst¹, Marc Gerspacher², Patricia Imbach-Weese², Robert Mah², Giorgio Caravatti², Pascal Furet², Christine Fritsch², Christian Schnell², Joachim Blanz², Francesca Blasco², Sandrine Desrayaud², Daniel A Guthy², Mark Knapp², Dorothee Arz², Jasmin Wirth², Esther Roehn-Carnemolla², Van Huy Luu²

Affiliations

¹ Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland. Electronic address: robin.fairhurst@novartis.com.
² Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.

PMID: 26199119
DOI: 10.1016/j.bmcl.2015.06.067

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.

Keywords: Kinase inhibitor; Oncology; Phosphatidylinositol-3-kinase-alpha.

MeSH terms

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
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Quinazolines / chemistry*
Quinazolines / pharmacokinetics
Quinazolines / pharmacology*
Quinazolines / therapeutic use
Structure-Activity Relationship
Thiazoles / chemistry*
Thiazoles / pharmacokinetics
Thiazoles / pharmacology*
Thiazoles / therapeutic use

Substances

Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Quinazolines
Thiazoles
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human