US20050261365A1 - Transthyretin stabilization - Google Patents

Transthyretin stabilization Download PDF

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US20050261365A1
US20050261365A1 US11/134,527 US13452705A US2005261365A1 US 20050261365 A1 US20050261365 A1 US 20050261365A1 US 13452705 A US13452705 A US 13452705A US 2005261365 A1 US2005261365 A1 US 2005261365A1
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ttr
dibenzofuran
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Jeffery Kelly
H. Petrassi
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Scripps Research Institute
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Definitions

  • the present invention relates to inhibitors of transthyretin amyloid fibril formation. More particularly, the invention relates to derivatized dibenzofurans as inhibitors of transthyretin amyloid fibril formation.
  • TTR transthyretin
  • Dibenzofuran-4,6-dicarboxylic acid core structures having an aromatic substituent appended onto the dibenzofuran ring at the C1 position using three different types of linkages are disclosed herein and shown to afford exceptional amyloidogenesis inhibitors that display increased affinity and greatly increased binding selectivity to TTR over all the other plasma proteins, relative to lead compound 1 (Purkey, H. E.; et al. Proc. Natl. Acad. Sci. USA 2001, 98, 5566-5571). It is further disclosed herein that these compounds function by imposing kinetic stabilization on the TTR tetramer.
  • Transthyretin (TTR) amyloidogenesis requires rate limiting tetramer dissociation and partial monomer denaturation to produce a misassembly competent species. This process has been followed by turbidity to identify transthyretin amyloidogenesis inhibitors including dibenzofuran-4,6-dicarboxylic acid (1).
  • An X-ray cocrystal structure of TTR•1 2 reveals that it only utilizes the outer portion of the two thyroxine binding pockets to bind to and inhibit TTR amyloidogenesis.
  • structure-based design was employed to append aryl substituents using three different chemical linkages at C1 of the dibenzofuran ring to complement the unused inner portion of the thyroxine binding pockets.
  • One aspect of the invention is directed to a compound represented by Formula I:
  • X is absent or is a diradical selected from the group consisting of —O—, —S—, and —NH—; and R 2 , R 3 , R 4 , and R 5 are radicals independently selected from the group consisting of —H, —OH, —F, —Cl, —Br, —CF 3 , and —CO 2 H.
  • the compound is represented by Formula II:
  • preferred embodiments may include species wherein R 2 is a radical selected from the group consisting of —H, —F, —Cl, and —CF 3 ; additional preferred embodiments may include species wherein R 4 is a radical selected from the group consisting of —H, —Cl, and —CO 2 H; additional preferred embodiments may include species wherein R 5 is a radical selected from the group consisting of —H, —F, and —Cl.
  • Preferred species of the subgenus of Formula II include compounds selected from the group represented by the following structures:
  • the compound is represented by Formula III:
  • preferred embodiments may include species wherein R 3 is a radical selected from the group consisting of —H, —F, —Cl, —Br, and —CF 3 ; additional preferred embodiments may include species wherein R 5 is a radical selected from the group consisting of —H, —F, —Cl, and —Br.
  • Preferred species of the subgenus of Formula III include compounds selected from the group represented by the following structures:
  • the compound is represented by Formula IV:
  • preferred embodiments may include species wherein R 2 is a radical selected from the group consisting of —H, —F, and —Cl; additional preferred embodiments may include species wherein R 3 is a radical selected from the group consisting of —H, —F, —Cl, —CF 3 , and —CO 2 H; additional preferred embodiments may include species wherein R 4 is a radical selected from the group consisting of —H, and —CO 2 H; additional preferred embodiments may include species wherein R 5 is a radical selected from the group consisting of —H, —F, —Cl, and —CF 3 .
  • Preferred species of the subgenus of Formula IV include compounds selected from the group represented by the following structures:
  • a further aspect of the invention is directed to a process comprising the step of contacting transthyretin with a concentration of a compound selected from Formulas I-IV, described above, sufficient for inhibiting amyloid fibril formation.
  • FIG. 1A illustrates an X-ray crystallographic structure of TTR•1 2 (Klabunde, T.; et al. Nature Struct. Biol. 2000, 7, 312-321).
  • FIG. 1B illustrates a line drawing representation of the design of the 1-substituted-dibenzofuran-4,6-dicarboxylic acids placed in the thyroxine binding pocket
  • X represents either an NH, O or direct C aryl -C aryl linkage
  • R represents the substituents of the aryl ring designed to complement TTR's inner binding cavity.
  • FIG. 2 illustrates a table highlighting the concentration dependent acid-substituted dibenzofuran activity against WT-TTR (3.6 ⁇ M) amyloid fibril formation (f.f.) at pH 4.4 (72 h).
  • FIG. 3 illustrates a chart showing a summary of dibenzofuran-based amyloid inhibition activity (3.6 ⁇ M) against WT-TTR (3.6 ⁇ M) fibril formation (pH 4.4, 72 h) and binding stoichiometry to TTR in human blood plasma.
  • FIG. 4 illustrates a scheme for the synthesis of 1-hydroxy-dibenzofuran-4,6-dicarboxylate dimethyl ester and the corresponding triflate.
  • FIG. 5 illustrates a scheme for the synthesis of 1-phenyl-, phenoxy-, and phenylamine-dibenzofuran-4,6-dicarboxylate dimethyl esters and the corresponding dicarboxylates.
  • FIG. 6 illustrates a chart showing dibenzofuran-based inhibitor activity (7.2 ⁇ M) against WT-TTR (3.6 ⁇ M) amyloid fibril formation (f.f.) at pH 4.4 (72 h).
  • FIG. 7 illustrates a table illustrating dibenzofuran plasma TTR binding stoichiometry plotted vs. fibril formation inhibition efficacy.
  • FIG. 8 illustrates a plot of the absorbance at 280 nm versus distance from the center in the sedimentation velocity study on TTR (3.6 ⁇ M) after being preincubated with 27 (7.2 ⁇ M) and after another incubation period where the pH was dropped to 4.4 for 72 h, a time frame that results in maximal amyloid formation in the absence of inhibitor.
  • FIG. 9 illustrates a plot of the absorbance at 280 nm versus distance from the center in the equilibrium ultracentrifugation studies on TTR (3.6 ⁇ M) after being preincubated with 27 (7.2 ⁇ M) and after another incubation period where the pH was dropped to 4.4 for 72 h, a time frame that results in maximal amyloid formation in the absence of inhibitor.
  • FIG. 10 illustrates a plot of the timecourse analysis of WT-TTR (3.6 ⁇ M) fibril formation mediated by partial acid denaturation in the absence ( ⁇ ) and presence of 7.2 ⁇ M ( ⁇ ) and 3.6 ⁇ M ( ⁇ ) inhibitors 25, 47, and 64, as measured by turbidity at 500 nm (see shading scheme within Figure to differentiate inhibitors).
  • FIG. 11 illustrates a plot of the timecourse analysis of WT-TTR (3.6 ⁇ M) tetramer dissociation (6.0 M urea) in the absence ( ⁇ ) and presence of 7.2 ⁇ M ( ⁇ ) and 3.6 ⁇ M ( ⁇ ) concentrations of inhibitors 25, 47, and 64 (see color scheme within Figure to differentiate inhibitors).
  • FIG. 7 shaded in gray contains dibenzofuran-based compounds that meet the criteria for high in vitro activity ( ⁇ 40% fibril formation) and high binding selectivity (>1 equiv bound to TTR in plasma).
  • the most important point is that the activity and binding selectivity of almost all of the dibenzofuran-based inhibitors, especially those in the gray box ( FIG. 7 ), are sufficient to kinetically stabilize TTR in plasma should they display desirable oral bioavailability, pharmacokinetic, and toxicity profiles.
  • inhibitor efficacy in vitro (3.6 ⁇ M) and inhibitor binding selectivity (10.8 ⁇ M) to TTR in plasma do not correlate ( FIG. 7 ).
  • Compounds that exhibit superior binding selectivity to TTR over all of the other plasma proteins should be excellent inhibitors of fibril formation.
  • excellent inhibitors need not display high TTR plasma binding selectivity.
  • Excellent inhibitors that display high TTR plasma binding selectivity are the most useful compounds in humans because these can selectively stabilize the TTR native state over the dissociative transition state and impart kinetic stabilization on TTR in a protein-rich biological fluid.
  • Their binding constants to TTR are important because the extent of kinetic stabilization is proportional to the binding constants.
  • dibenzofuran inhibitors display unprecedented binding selectivity and inhibitor potency as a group relative to inhibitors characterized heretofore (Hammarstrom, P.; et al. Science 2003, 299, 713-716; Klabunde, T.; et al. Nature Struct. Biol. 2000, 7, 312-321; Razavi, H.; et al. Angew. Chem. 2003, 42, 2758-2761; Miroy, G. J.; et al. Proc. Natl. Acad. Sci. USA 1996, 93, 15051-15056; Peterson, S. A.; et al. Proc. Natl. Acad. Sci. USA 1998, 95, 12956-12960; Baures, P.
  • TTR is the tertiary carrier of T 4 , more than 99% of its binding sites are unoccupied; therefore, inhibitor binding to TTR should not perturb T 4 homeostasis.
  • the C1-substituted dibenzofuran-based TTR amyloidogenesis inhibitors are promising because of their amyloid inhibition potency in vitro, their superb binding selectivity to TTR in plasma, their slow TTR dissociation rates (which must be the case to see high plasma selectivity by the method utilized herein), their ability to impose kinetic stabilization upon the TTR tetramer, their chemical stability in plasma, and their chemical stability at low pH (making them excellent candidates for oral administration).
  • These inhibitors are useful for the treatment of TTR amyloid diseases, including SSA, FAP, and FAC, because kinetic stabilization of TTR is known to ameliorate FAP (Hammarstrom, P.; et al.
  • FIG. 1A depicts the two symmetry equivalent binding modes of 1 (green and yellow) within one of the TTR thyroxine binding sites, the surface of which is outlined in gray (Klabunde, T.; et al. Nature Struct. Biol. 2000, 7, 312-321).
  • the carboxylates at the 4 and 6 positions make electrostatic interactions with the ⁇ -NH 3 + groups of Lys 15 and 15′ at the entrance to the thyroxine binding site. Removal of one of the carboxylates renders dibenzofuran much less active, as does varying the carboxylate spacing from the aromatic ring in most cases ( FIG. 2 ).
  • the dibenzofuran ring nicely complements the shape and hydrophobicity of the outer portion of the thyroxine binding cavity.
  • Inspection of the TTR•1 2 crystal structure in FIG. 1A reveals that there is a large amount of unoccupied volume in the inner portion of the thyroxine binding site with 1 bound.
  • a substituent such as an aryl ring, could be projected into the inner portion of the binding site by attaching it to the C1 position of the dibenzofuran ring of 1.
  • such a substituent could be linked to a dibenzofuran scaffold through a heteroatom (N or O) or directly via a C aryl -C aryl bond (not shown).
  • Aromatic substituents ( FIG. 3 ) were chosen to interact with either the halogen binding pockets or hydrogen bonding substructures within the inner cavity based on the envisioned orientation of the phenyl ring in the inner binding cavity and previous SAR data from other chemical series thought to position their aryl rings similarly (Hammarstrom, P.; et al. Science 2003, 299, 713-716; Klabunde, T.; et al. Nature Struct. Biol. 2000, 7, 312-321; Razavi, H.; et al. Angew Chem 2003, 42, 2758-2761; Miroy, G. J.; et al. Proc. Natl. Acad. Sci.
  • Inhibition efficacy (compounds 24-38, 44-48, and 60-70) was first evaluated using recombinant TTR in a partially denaturing buffer that promotes amyloidogenesis (pH 4.4, 37° C.). As a follow up, the ability of effective inhibitors to bind to TTR selectively over all the other proteins in human plasma was assessed.
  • TTR amyloid inhibition efficacy was probed using a stagnant fibril formation assay described previously, wherein partial denaturation was triggered by acidification (pH 4.4, 37° C.) (Colon, W.; Kelly, J. W. Biochemistry 1992, 31, 8654-8660). Briefly, a test compound (7.2 or 3.6 ⁇ M) is incubated with TTR (3.6 ⁇ M) for 30 min in pH 7 buffer. Amyloidogenesis is then initiated by lowering to pH 4.4, where maximal fibril formation is observed with WT-TTR after 72 h (37° C.).
  • FIG. 6 (at 7.2 ⁇ M there is enough test compound added to occupy both of the binding sites of TTR (TTR•I 2 ), provided their dissociation constants are both in the low nM range at pH 4.4).
  • Small molecules typically bind to TTR with negative cooperativity, hence K d1 and K d2 are often are separated by one or two orders of magnitude. Therefore, when both the ligand and TTR are at equal concentrations, a population of TTR•I, TTR•I 2 and unliganded TTR is observed, dictated by the dissociation constants.
  • Inhibitor binding selectivity to TTR in human blood plasma was assessed using a previously established antibody capture method (Purkey, H. E.; et al. Proc. Natl. Acad. Sci. USA 2001, 98, 5566-5571).
  • inhibitors (10.8 ⁇ M, ⁇ 2-3 ⁇ the natural concentration of TTR) are incubated in human blood plasma for 24 h at 37° C. Quenched sepharose resin is then added to the plasma to remove any small molecules that would bind to the resin as opposed to TTR. TTR and any TTR-bound small molecule is then immunocaptured using a polyclonal TTR antibody covalently attached to sepharose resin.
  • the antibody-TTR complex is dissociated at high pH and analyzed by RP-HPLC.
  • the relative stoichiometry between TTR and inhibitor is then calculated from their HPLC peak areas using standard curves. Wash-associated losses are typically observed for inhibitors that have high dissociation rates; therefore, this analysis can underestimate their true binding stoichiometry, but gives faithful results for compounds exhibiting low dissociation constants and off-rates. Twenty-one inhibitors exhibit a binding stoichiometry exceeding one (two being the maximal binding stoichiometry), nineteen of which exhibit ⁇ 40% fibril formation at a concentration of 3.6 ⁇ M ( FIG. 7 , shaded box).
  • TTR quaternary structure by analytical ultracentrifugation after a preincubation period of 72 h under amyloidogenic conditions (pH 4.4, 37° C.).
  • TTR 3.6 ⁇ mM
  • FIG. 8 sedimentation velocity
  • FIG. 9 equilibrium analytical ultracentrifugation
  • TTR tetramer dissociation The ability of these inhibitors to impose kinetic stability on tetrameric TTR is best evaluated by assessing the rate of TTR tetramer dissociation (Hammarstrom, P.; et al. Science 2003, 299, 713-716; Hammarstrom, P.; et al. Proc. Natl. Acad. Sci. USA 2002, 99, 16427-16432). Under acidic conditions tetramer dissociation leads to amyloidogenesis, whereas in the presence of chaotropes (6M urea), tetramer dissociation leads to monomer unfolding.
  • inhibitors 25, 47 and 64 representing the three structural classes of dibenzofuran-based inhibitors
  • TTR amyloidogenesis mediated by partial acidification is dramatically slowed in a dose-dependent fashion relative to control (no inhibitor) by 25, 47 and 64 ( FIG. 4A ).
  • the rate of TTR tetramer dissociation in 6M urea is easily monitored by linking the slow quaternary structural changes to rapid tertiary structural changes that are easily monitored by spectroscopic methods (Hammarstrom, P.; et al. Proc. Natl. Acad. Sci. USA 2002, 99, 16427-16432).
  • the pH was then adjusted to 4.4 with addition of 500 ⁇ L of acidic buffer (100 mM acetate, 100 mM KCl, 1 mM EDTA, pH 4.2), and the final 1 mL solutions were vortexed again and incubated in the dark at 37° C. without agitation.
  • acidic buffer 100 mM acetate, 100 mM KCl, 1 mM EDTA, pH 4.2
  • the solutions were vortexed and the turbidity at 500 nm was measured.
  • Control samples containing 5 ⁇ L of pure DMSO were prepared and analyzed as above for comparison. Small molecule and TTR control samples were prepared in groups of 10 to prevent disturbance of the cuvettes during incubation. Samples were discarded after their turbidities were measured.
  • urea buffer (6.67 M urea, 50 mM sodium phosphate, 100 mM KCl, 1 mM EDTA, pH 7.2), and the final 1 mL solutions were vortexed again and incubated in the dark at 25° C. without agitation.
  • the circular dichroism spectra were measured between 218 and 215 nm, with scanning every 0.5 nm and averaging for 5 s. After measurements were taken, samples were returned to their respective eppendorf tubes and incubation was continued.
  • Control samples containing 7.2 ⁇ L of 10% DMSO in EtOH were prepared and analyzed as above for comparison.
  • the CD amplitude values were averaged between 215 and 218 nm to determine the extent of ⁇ -sheet loss throughout the experiment.
  • TTR tetramer dissociation is linked to the rapid ( ⁇ 500,000 ⁇ faster) monomer denaturation as measured through this ⁇ -sheet loss (Hammarstrom, P.; et al. Proc. Natl. Acad. Sci. USA 2002, 99, 16427-16432).
  • the flask was cooled again to ⁇ 78° C. as described above and a 15 psi stream of CO 2 (g) was bubbled through the reaction suspension (the CO 2 was dried by passing it through a drying tube containing activated silica). Following initial addition of CO 2 (g), the cooling bath was removed and the reaction was stirred for 30 min. The reaction mixture was poured into a 1 L beaker containing ice water (50 mL). The solution was brought to pH 9 by the slow addition of 0.05 M KOH, and then cooled to 0° C. with an ice/H 2 O bath. The solution was acidified to pH 2 with 0.5 M HCl causing a white solid to precipitate.
  • the aqueous suspension (pH 2) was transferred into a 1 L separatory funnel and extracted with EtOAc (5 ⁇ 50 mL). The combined extracts were dried with MgSO 4 and concentrated under reduced pressure to afford the crude diacid as an oil.
  • the 100 mL flask containing the crude diacid was equipped with a stir bar, capped with a septum and evacuated. The flask was then back-filled with argon. Anhydrous MeOH (2 mL) and ACS reagent grade benzene (8 mL) were added via syringe.
  • Trimethylsilyidiazomethane (TMSCHN 2 ; 2.5 mL of a 2 M solution in hexanes, 5 mmol) was added slowly via syringe through the septum. Upon completion of the TMSCHN 2 addition the reaction was stirred for 10 min and the solvent removed under reduced pressure to afford a red oil. The residue was purified by flash chromatography over silica (15% EtOAc in hexanes) to afford 0.36 g (43%) of 6 as a white solid.
  • MALDI-FTMS 479.1874 m/z (M+Na) + , C 25 H 32 O 6 SiNa requires 479.1860.
  • the biaryl ether coupling was directly adapted from the procedures reported by Chan and Evans.
  • a 20 mL scintillation vial equipped with a magnetic stir bar was charged with phenol 7 (150 mg, 0.50 mmol), copper (II) acetate (91 mg, 0.5 mmol), freshly activated 4 ⁇ molecular sieves ( ⁇ 250 mg), and phenylboronic acid (180 mg, 1.5 mmol).
  • Dichloromethane (5 mL) was added followed by pyridine (201 ⁇ L, 2.5 mmol), resulting in an aqua colored suspension.
  • the cap was very loosely applied such that the reaction suspension was partly open to the atmosphere.
  • the reaction was monitored by TLC.
  • Methyl ester 9 (25 mg, 0.067 mmol) was saponified in THF: MeOH: H 2 O (3:1:1, 1 mL) in a 20 mL scintillation vial equipped with a stir bar. LiOH.H 2 O (22 mg, 0.53 mmol) was added to the suspension and the reaction was allowed to stir until completion (typically 4 h) as determined by TLC or analytical reverse phase HPLC monitoring. The reaction mixture was diluted with brine (2 mL) and acidified to pH 2 with 1 M HCl (pH paper) resulting in a biphasic solution. The upper layer (THF) was removed and the aqueous layer was extracted with THF (3 ⁇ 3 mL).
  • FIG. 1A shows an X-ray crystallographic structure of TTR•1 2 (Klabunde, T.; et al. Nature Struct. Biol. 2000, 7, 312-321).
  • the residues lining the binding site are displayed as stick models (oxygen in red, nitrogen in blue, and carbon in gray), with the protein's Connolly surface depicted in gray.
  • Compound 1 is shown in both of its C 2 symmetry equivalent binding modes (yellow and green).
  • the binding channel has 3 sets of depressions referred to as the halogen binding pockets (HBPs) because they interact with the iodines of thyroxine.
  • HBPs halogen binding pockets
  • Compound 1 occupies only the outer portion of the binding pocket and fills both HBP1 and 1′.
  • the carboxylic acids of 1 are in proximity to the e-NH 3 + of K15 and K15′.
  • FIG. 1B shows a line drawing representation of the design of the 1-substituted-dibenzofuran-4,6-dicarboxylic acids placed in the thyroxine binding pocket where X represents either an NH, O or direct C aryl -C aryl linkage. R represents the substituents of the aryl ring designed to complement TTR's inner binding cavity.
  • FIG. 2 is a table highlighting the concentration dependent acid-substituted dibenzofuran activity against WT-TTR (3.6 ⁇ M) amyloid fibril formation (f.f.) at pH 4.4 (72 h). Values represent the extent of f.f. and thus inhibitor efficacy relative to WT-TTR fibril formation in the absence of inhibitor (assigned to be 100%): complete inhibition is equivalent to 0% f.f.
  • FIG. 3 is a chart showing a summary of dibenzofuran-based amyloid inhibition activity (3.6 mM) against WT-TTR (3.6 mM) fibril formation (pH 4.4, 72 h) and binding stoichiometry to TTR in human blood plasma.
  • % Fibril formation (f.f.) values in the middle column represent the extent of f.f., and thus inhibitor efficacy, relative to WT-TTR f.f. in the absence of inhibitor (assigned to be 100%). Complete inhibition is equivalent to 0% f.f.
  • the right column depicts the observed stoichiometry of inhibitor (dosed at 10.8 mM, ⁇ 2-3 ⁇ the concentration of plasma TTR) bound to TTR in blood plasma as determined using the antibody capture method.
  • FIG. 4 is a scheme for the synthesis of 1-hydroxy-dibenzofuran-4,6-dicarboxylate dimethyl ester and the corresponding triflate: a) K 3 [Fe(CN) 6 ], KOH, H 2 O, benzene; b) AlCl 3 , toluene, 33% for both steps; c) TIPSCI, DMAP, CH 2 Cl 2 , 77%; d) sec-BuLi, Et 2 O, ⁇ 78° C., gaseous CO 2 , TMSCHN 2 , 43%; e) TBAF, THF, 97%; f) Tf 2 O, pyridine, 92%.
  • FIG. 5 is a scheme for the synthesis of 1-phenyl-, phenoxy-, and phenylamine-dibenzofuran-4,6-dicarboxylate dimethyl esters and the corresponding dicarboxylates: a) Pd 2 (DBA) 3 , ( ⁇ )binap, Cs 2 CO 3 , toluene 100° C.; b) LiOH—H 2 O, THF/MeOH/H 2 O (3:1:1); c) Cu II (OAc) 2 , pyridine, 4 ⁇ MS, CH 2 Cl 2 ; d) Pd(PPh 3 ) 4 , LiCl, aq. Na 2 CO 3 , toluene, MeOH, 80° C.
  • FIG. 6 is a chart showing dibenzofuran-based inhibitor activity (7.2 ⁇ M) against WT-TTR (3.6 ⁇ M) amyloid fibril formation (f.f.) at pH 4.4 (72 h). Values represent the extent of f.f. and thus inhibitor efficacy relative to WT-TTR fibril formation in the absence of inhibitor (assigned to be 100%): complete inhibition is equivalent to 0% f.f.
  • FIG. 7 is a table illustrating dibenzofuran plasma TTR binding stoichiometry plotted vs. fibril formation inhibition efficacy.
  • the lightly shaded area corresponds to the definitions of high activity and high selectivity ( ⁇ 40% fibril formation and a binding stoichiometry >1), while the darkly shaded area corresponds to exceptional compounds ( ⁇ 30% fibril formation and a binding stoichiometry >1.25).
  • Data points identify the three different linkers: NH ( ⁇ ), ⁇ ( ), and direct C aryl -C aryl linkage ( ⁇ ).
  • Dibenzofuran-4,6-dicarboxylic acid (1) data point ( ⁇ ) shown for comparison.
  • FIG. 8 is a plot of the absorbance at 280 nm versus distance from the center in the sedimentation velocity study on TTR (3.6 mM) after being preincubated with 27 (7.2 mM) and after another incubation period where the pH was dropped to 4.4 for 72 h, a time frame that results in maximal amyloid formation in the absence of inhibitor.
  • Velocity analysis overlay of data sets taken 15 min apart at 50,000 rpm. The data (symbols) fit to a single ideal species model (solid line) with MW 57.1 ⁇ 0.2 kDa.
  • FIG. 9 is a plot of the absorbance at 280 nm versus distance from the center in the equilibrium ultracentrifugation studies on TTR (3.6 mM) after being preincubated with 27 (7.2 mM) and after another incubation period where the pH was dropped to 4.4 for 72 h, a time frame that results in maximal amyloid formation in the absence of inhibitor.
  • Equilibrium analysis equilibrium concentration gradient observed after a 24 h application of centrifugal force to the sample employing at a speed of 17,000 rpm.
  • the data ( ⁇ ) fit to a single ideal species model (solid line) with MW 55.0 ⁇ 0.2 kDa.
  • the residuals, the difference between experimental and fitted data, are shown in the inset.
  • FIG. 10 is a plot of the timecourse analysis of WT-TTR (3.6 ⁇ M) fibril formation mediated by partial acid denaturation in the absence ( ⁇ ) and presence of 7.2 ⁇ M ( ⁇ ) and 3.6 ⁇ M ( ⁇ ) inhibitors 25, 47, and 64, as measured by turbidity at 500 nm (see color scheme within Figure to differentiate inhibitors). It is hard to discern which compound is most efficacious in the black and white plot. At the end of the plot or after 169 hours have passed, compound 47 shows the most fibrils formed followed by compound 64 followed by compound 25.
  • FIG. 11 is a plot of the timecourse analysis of WT-TTR (3.6 ⁇ M) tetramer dissociation (6.0 M urea) in the absence ( ⁇ ) and presence of 7.2 ⁇ M ( ⁇ ) and 3.6 ⁇ M ( ⁇ ) concentrations of inhibitors 25, 47, and 64 (see color scheme within Figure to differentiate inhibitors).
  • Slow tetramer dissociation is not detectable by far-UV CD spectroscopy, but this process is linked to rapid ( ⁇ 500,000 ⁇ faster) monomer denaturation as monitored by loss of ⁇ -sheet content easily followed by circular dichroism spectroscopy. It is hard to discern which compound is most efficacious in the black and white plot.
  • compound 25 is most effective in dissociating tetramers followed by compound 64 followed by compound 47.

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