Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores.
Carboranes represent a potentially rich but underutilized class of inorganic and catabolism-inert pharmacophores. The regioselectivity and ease of derivatization of carboranes allows for facile syntheses of a wide variety of novel structures. The steric bulk, rigidity, and ease of B- and C-derivatization and lack of pi-interactions associated with hydrophobic carboranes may be exploited to enhance the selectivity of previously identified bioactive molecules. Transthyretin (TTR) is a thyroxine-transport protein found in the blood that has been implicated in a variety of amyloid related diseases. Previous investigations have identified a variety of nonsteroidal antiinflammatory drugs (NSAIDs) and structurally related derivatives that imbue kinetic stabilization to TTR, thus inhibiting its dissociative fragmentation and subsequent aggregation to form putative toxic amyloid fibrils. However, the cyclooxygenase (COX) activity associated with these pharmaceuticals may limit their potential as long-term therapeutic agents for TTR amyloid diseases. Here, we report the synthesis and evaluation of carborane-containing analogs of the promising NSAID pharmaceuticals previously identified. The replacement of a phenyl ring in the NSAIDs with a carborane moiety greatly decreases their COX activity with the retention of similar efficacy as an inhibitor of TTR dissociation. The most promising of these compounds, 1-carboxylic acid-7-[3-fluorophenyl]-1,7-dicarba-closo-dodecaborane, showed effectively no COX-1 or COX-2 inhibition at a concentration more than an order of magnitude larger than the concentration at which TTR dissociation is nearly completely inhibited. This specificity is indicative of the potential for the exploitation of the unique properties of carboranes as potent and selective pharmacophores.
Julius
Richard L
RL
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.
Farha
Omar K
OK
Chiang
Janet
J
Perry
L Jeanne
LJ
Hawthorne
M Frederick
MF
D000682:Amyloid / Q000096:biosynthesis / Q000187:drug effects*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001880:Boranes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004061:Diflunisal / Q000737:chemistry / Q000494:pharmacology; D005439:Flufenamic Acid / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D011228:Prealbumin / Q000037:antagonists & inhibitors*
D000682:Amyloid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001880:Boranes; D011228:Prealbumin; D005439:Flufenamic Acid; D004061:Diflunisal; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2