Design, synthesis, and evaluation of oxazole transthyretin amyloidogenesis inhibitors.
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.
Razavi
Hossein
H
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.
Powers
Evan T
ET
Purkey
Hans E
HE
Adamski-Werner
Sara L
SL
Chiang
Kyle P
KP
Dendle
Maria T A
MT
Kelly
Jeffery W
JW
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
D000682:Amyloid; D001798:Blood Proteins; D010080:Oxazoles; D011228:Prealbumin