title: Structure-activity relationships of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors: investigations of various 6,5-heterocycles to improve metabolic stability.
abstract: N-(6-(6-Chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (1) is a potent and efficacious inhibitor of PI3Kα and mTOR in vitro and in vivo. However, in hepatocyte and in vivo metabolism studies, 1 was found to undergo deacetylation on the 2-amino substituent of the benzothiazole. As an approach to reduce or eliminate this metabolic deacetylation, a variety of 6,5-heterocyclic analogues were examined as an alternative to the benzothiazole ring. Imidazopyridazine 10 was found to have similar in vitro potency and in vivo efficacy relative to 1, while only minimal amounts of the corresponding deacetylated metabolite of 10 were observed in hepatocytes.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. mstec@amgen.com
authors.forename: Markian M
authors.initials: MM
authors.lastname: Stec
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.forename: Shon K
authors.initials: SK
authors.lastname: Booker
authors.forename: Sean
authors.initials: S
authors.lastname: Caenepeel
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Freeman
authors.forename: Jian
authors.initials: J
authors.lastname: Jiang
authors.forename: Hongyu
authors.initials: H
authors.lastname: Liao
authors.forename: John
authors.initials: J
authors.lastname: McCarter
authors.forename: Erin L
authors.initials: EL
authors.lastname: Mullady
authors.forename: Tisha
authors.initials: T
authors.lastname: San Miguel
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.forename: Nuria
authors.initials: N
authors.lastname: Tamayo
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Kevin
authors.initials: K
authors.lastname: Yang
authors.forename: Leeanne P
authors.initials: LP
authors.lastname: Zalameda
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhang
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hughes
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011724:Pyridazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010080:Oxazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011724:Pyridazines; D011725:Pyridines; D013449:Sulfonamides; D013844:Thiazoles; D058570:TOR Serine-Threonine Kinases