title: Discovery of N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine, a potent apoptosis inducer and efficacious anticancer agent with high blood brain barrier penetration.
abstract: As a continuation of our structure-activity relationship (SAR) studies on 4-anilinoquinazolines as potent apoptosis inducers and to identify anticancer development candidates, we explored the replacement of the 2-Cl group in our lead compound 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (6b, EP128265, MPI-0441138) by other functional groups. This SAR study and lead optimization resulted in the identification of N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (6h, EP128495, MPC-6827) as an anticancer clinical candidate. Compound 6h was found to be a potent apoptosis inducer with EC(50) of 2 nM in our cell-based apoptosis induction assay. It also has excellent blood brain barrier penetration, and is highly efficacious in human MX-1 breast and other mouse xenograft cancer models.
authors.affiliation: EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, California 92121, USA.
authors.forename: Nilantha
authors.initials: N
authors.lastname: Sirisoma
authors.forename: Azra
authors.initials: A
authors.lastname: Pervin
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Songchun
authors.initials: S
authors.lastname: Jiang
authors.forename: J Adam
authors.initials: JA
authors.lastname: Willardsen
authors.forename: Mark B
authors.initials: MB
authors.lastname: Anderson
authors.forename: Gary
authors.initials: G
authors.lastname: Mather
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Pleiman
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis; D001812:Blood-Brain Barrier / Q000378:metabolism*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C522974:verubulin