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2‐Aminothiazoles with Improved Pharmacotherapeutic Properties for Treatment of Prion Disease
Author(s) -
Li Zhe,
Silber B. Michael,
Rao Satish,
Gever Joel R.,
Bryant Clifford,
GallardoGodoy Alejandra,
Dolghih Elena,
Widjaja Kartika,
Elepano Manuel,
Jacobson Matthew P.,
Prusiner Stanley B.,
Renslo Adam R.
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300007
Subject(s) - potency , bioavailability , chemistry , amine gas treating , amide , pharmacokinetics , pharmacology , microsome , stereochemistry , prion protein , combinatorial chemistry , in vitro , disease , biochemistry , biology , medicine , organic chemistry
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/EC 50 ratios at least tenfold greater than that of compound 1 .
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