title: 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.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland. Electronic address: robin.fairhurst@novartis.com.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Fairhurst
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Gerspacher
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Imbach-Weese
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Mah
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Caravatti
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Fritsch
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Joachim
authors.initials: J
authors.lastname: Blanz
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Blasco
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Guthy
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Arz
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Wirth
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Esther
authors.initials: E
authors.lastname: Roehn-Carnemolla
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Van Huy
authors.initials: VH
authors.lastname: Luu
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013844:Thiazoles; C484760:PIK3CA protein, human
keywords: Kinase inhibitor; Oncology; Phosphatidylinositol-3-kinase-alpha