title: Sulfonyl-morpholino-pyrimidines: SAR and development of a novel class of selective mTOR kinase inhibitor.
abstract: High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine 1 as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3Kα. Library preparation of related analogs allowed the establishment of additional SAR understanding and in particular the requirement for a key hydrogen bond donor motif at the 4-position of the phenyl ring in compounds such as indole 19. Isosteric replacement of the indole functionality led to the identification of urea compounds such as 32 that show good levels of mTOR inhibition in both enzyme and cellular assays.
authors.affiliation: AstraZeneca, Oncology Innovative Medicines, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. ray.finlay@astrazeneca.com
authors.forename: M Raymond V
authors.initials: MR
authors.lastname: Finlay
authors.forename: David
authors.initials: D
authors.lastname: Buttar
authors.forename: Susan E
authors.initials: SE
authors.lastname: Critchlow
authors.forename: Allan P
authors.initials: AP
authors.lastname: Dishington
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Fillery
authors.forename: Eric
authors.initials: E
authors.lastname: Fisher
authors.forename: Steve C
authors.initials: SC
authors.lastname: Glossop
authors.forename: Mark A
authors.initials: MA
authors.lastname: Graham
authors.forename: Trevor
authors.initials: T
authors.lastname: Johnson
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Lamont
authors.forename: Simon
authors.initials: S
authors.lastname: Mutton
authors.forename: Paula
authors.initials: P
authors.lastname: Perkins
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Pike
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Slater
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones; D058570:TOR Serine-Threonine Kinases; D014508:Urea; C546842:MTOR protein, human