2‐Aminothiazoles with Improved Pharmacotherapeutic Properties for Treatment of Prion Disease |
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| Authors: | Prof?Dr Zhe Li Prof?Dr Satish Rao Prof?Dr Joel R Gever Clifford Bryant Dr Alejandra Gallardo‐Godoy Dr Elena Dolghih Kartika Widjaja Manuel Elepano Prof?Dr Matthew P Jacobson Prof?Dr Stanley B Prusiner Prof?Dr Adam R Renslo |
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| Affiliation: | 1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA);2. Department of Neurology, University of California, San Francisco, San Francisco, CA 94143 (USA);3. Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA 94143 (USA);4. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143 (USA) |
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| 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 PrPSc. 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 . |
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| Keywords: | 2‐aminothiazoles neurological agents pharmacokinetic optimization prion disease structure– activity relationships |
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