Design and synthesis of oxadiazolidinediones as inhibitors of plasminogen activator inhibitor-1

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 13, 2004, Pages 3477-3480

  Gopalsamy, Ariamala ^a   Kincaid, Scott L ^a   Ellingboe, John W ^a   Groeling, Thomas M ^b   Antrilli, Thomas M ^b   Krishnamurthy, Girija ^a   Aulabaugh, Ann ^a   Friedrichs, Gregory S ^b   Crandall, David L ^b  

^a WYETH RESEARCH   (United States)

^b PFIZER INC   (United States)

Author keywords

Oxadiazolidine diones; PAI 1 inhibitor; Parallel synthesis

Indexed keywords

FIBRINOLYTIC AGENT; OXADIAZOLIDINEDIONE DERIVATIVE; PLASMINOGEN ACTIVATOR INHIBITOR 1; UNCLASSIFIED DRUG;

ARTICLE; DRUG DESIGN; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SYNTHESIS; STRUCTURE ACTIVITY RELATION;

DRUG DESIGN; HUMANS; INHIBITORY CONCENTRATION 50; ISOMERISM; MICROSCOPY, FLUORESCENCE; OXAZOLIDINONES; PLASMINOGEN ACTIVATOR INHIBITOR 1; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 2942624338     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.04.058     Document Type: Article

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20. Determination of PAI-1 inhibition of tPA activity: Test compounds were dissolved in DMSO at a final concentration of 10 mM, then diluted 100 × in physiologic buffer. The inhibitory assay was initiated by the addition of test compound (1-100 μM final concentration, maximum DMSO concentration of 0.2%) in a pH 6.6 buffer containing 140 nM recombinant human plasminogen activator inhibitor-1 (PAI-1; Molecular Innovations, Royal Oak, MI). Following a 1 h incubation at room temperature, 70 nM of recombinant human tissue plasminogen activator (tPA) was added, and the combination of test compound, PAI-1 and tPA was incubated for an additional 30 min. Following the second incubation, Spectrozyme-tPA (American Diagnostica, Greenwich, CT), a chromogenic substrate for tPA, was added and absorbance read at 405 nm at 0 and 60 min. Relative PAI-1 inhibitory activity was equal to the residual tPA activity in the test compound/PAI-1 treatment. Control treatments include the complete inhibition of tPA by PAI-1 at the molar ratio employed (2:1), and the absence of any effect of the test compound on tPA alone
21. Direct binding to PAI-1: Fluorescence spectroscopy was used to determine the binding of 5 to recombinant human PAI-1. The changes in the quantum yield of the protein were used to determine the binding affinity of 5 to PAI-1 using a Jobin Yvon fluorometer. A fixed concentration of the protein was serially titrated with increasing concentrations of 5. The intrinsic fluorescence of the protein was measured at 335 nm using an excitation wavelength of 295 nm
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23. Compounds were purified by HPLC and the purity was > 90%. LC conditions: HP 1100, 23°C, 10 μL injected; column: YMC-ODS-A 4.6 × 5.0 5 μm; gradient A: 0.05% TFA/water, B: 0.05% TFA/acetonitrile; time 0 and 1 min: 98% A and 2% B; 7 min: 10% A and 90% B; 8 min: 10% A and 90% B; 8.9 min: 98% A and 2% B; post time 1 min; flow rate 2.5 mL/min; detection: 215 and 254 nm, DAD. Semi-Prep HPLC: Gilson with Unipoint software; Column: Phenomenex C18 Luna 21.6 mm × 60 mm, 5 μM; solvent A: water (0.02% TFA buffer); solvent B: acetonitrile (0.02 % TFA buffer); solvent gradient: time 0: 5% B; 2.5 min: 5% B; 12 min: 95% B; hold 95% B 3 min; flow rate: 22.5 mL/min; detection: 215 and 254 nm
24. During the reduction of the α, β-unsaturated oxime only saturated hydroxyl amines were obtained during the synthesis of analogues 36 and 37