Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies.
To develop potent and highly selective transthyretin (TTR) amyloidogenesis inhibitors, it is useful to systematically optimize the three substructural elements that compose a typical TTR kinetic stabilizer: the two aryl rings and the linker joining them. Herein, we evaluated 40 bisaryl molecules based on 10 unique linker substructures to determine how these linkages influence inhibitor potency and selectivity. These linkers connect one unsubstituted aromatic ring to either a 3,5-X 2 or a 3,5-X 2-4-OH phenyl substructure (X = Br or CH 3). Coconsideration of amyloid inhibition and ex vivo plasma TTR binding selectivity data reveal that direct connection of the two aryls or linkage through nonpolar E-olefin or -CH 2CH 2- substructures generates the most potent and selective TTR amyloidogenesis inhibitors exhibiting minimal undesirable binding to the thyroid hormone nuclear receptor or the COX-1 enzyme. Five high-resolution TTR.inhibitor crystal structures (1.4-1.8 A) provide insight into why such linkers afford inhibitors with greater potency and selectivity.
Johnson
Steven M
SM
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, BCC 265, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Connelly
Stephen
S
Wilson
Ian A
IA
Kelly
Jeffery W
JW
D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001669:Biochemical Phenomena; D001671:Biochemistry; D003432:Cross-Linking Reagents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D013329:Structure-Activity Relationship
D000682:Amyloid; D003432:Cross-Linking Reagents; D016861:Cyclooxygenase Inhibitors; D011228:Prealbumin; D011988:Receptors, Thyroid Hormone; D051545:Cyclooxygenase 1