title: Design, synthesis, and evaluation of oxazole transthyretin amyloidogenesis inhibitors.
abstract: Ten oxazoles bearing a C(4) carboxyl group were synthesized and evaluated as transthyretin (TTR) amyloid fibril inhibitors. Substituting aryls at the C(2) position of the oxazole ring reveals that a 3,5-dichlorophenyl substituent significantly reduced amyloidogenesis. The efficacy of these inhibitors was enhanced further by installing an ethyl, a propyl, or a CF(3) group at the C(5) position. The CF(3) substitution at C(5) also improves the TTR binding selectivity over all the other proteins in human blood.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, BCC265, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Razavi
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.forename: Sara L
authors.initials: SL
authors.lastname: Adamski-Werner
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Chiang
authors.forename: Maria T A
authors.initials: MT
authors.lastname: Dendle
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D001798:Blood Proteins / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011228:Prealbumin / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000682:Amyloid; D001798:Blood Proteins; D010080:Oxazoles; D011228:Prealbumin