title: 2-Aminothiazoles with improved pharmacotherapeutic properties for treatment of prion disease.
abstract: Recently, we described the aminothiazole lead (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine (1), which exhibits many desirable properties, including excellent stability in liver microsomes, oral bioavailability of ∼40 %, and high exposure in the brains of mice. Despite its good pharmacokinetic properties, compound 1 exhibited only modest potency in mouse neuroblastoma cells overexpressing the disease-causing prion protein PrP(Sc) . Accordingly, we sought to identify analogues of 1 with improved antiprion potency in ScN2a-cl3 cells while retaining similar or superior properties. Herein we report the discovery of improved lead compounds such as (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine and cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide, which exhibit brain exposure/EC50 ratios at least tenfold greater than that of compound 1.
authors.affiliation: Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: B Michael
authors.initials: BM
authors.lastname: Silber
authors.forename: Satish
authors.initials: S
authors.lastname: Rao
authors.forename: Joel R
authors.initials: JR
authors.lastname: Gever
authors.forename: Clifford
authors.initials: C
authors.lastname: Bryant
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gallardo-Godoy
authors.forename: Elena
authors.initials: E
authors.lastname: Dolghih
authors.forename: Kartika
authors.initials: K
authors.lastname: Widjaja
authors.forename: Manuel
authors.initials: M
authors.lastname: Elepano
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011257:Pregnancy Proteins / Q000096:biosynthesis; D017096:Prion Diseases / Q000188:drug therapy* / Q000378:metabolism; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C057074:Plfr protein, mouse; D011257:Pregnancy Proteins; D013844:Thiazoles; C004483:2-aminothiazole