Design, synthesis, and biological activity of piperidine diamine derivatives as factor Xa inhibitor

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 2, 2008, Pages 782-787

  Mochizuki, Akiyoshi ^a   Nakamoto, Yumi ^a   Naito, Hiroyuki ^a   Uoto, Kouichi ^a   Ohta, Toshiharu ^a  

^a DAIICHI SANKYO CO   (Japan)

Author keywords

Anticoagulant; cis Piperidine diamine derivative; Factor Xa inhibitor

Indexed keywords

2 [4 [(1 ACETIMIDOYL 3 PYRROLIDINYL)OXY]PHENYL] 3 (7 AMIDINO 2 NAPHTHYL)PROPIONIC ACID; BLOOD CLOTTING FACTOR 10A INHIBITOR; CYCLOHEXANE DERIVATIVE; PIPERIDINE DERIVATIVE;

ANIMAL EXPERIMENT; ANTICOAGULATION; AREA UNDER THE CURVE; ARTICLE; BIOLOGICAL ACTIVITY; DRUG CLEARANCE; DRUG DESIGN; DRUG HALF LIFE; DRUG SOLUBILITY; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN TISSUE; NONHUMAN; RAT;

ADMINISTRATION, ORAL; ANIMALS; AREA UNDER CURVE; DIAMINES; DRUG DESIGN; FACTOR XA; HAPLORHINI; HUMANS; MICROSOMES, LIVER; PIPERIDINES; RATS; SERINE PROTEINASE INHIBITORS;

RATTUS;

EID: 38149041703     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.11.037     Document Type: Article

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46. 50 value was obtained by plotting the inhibitor concentration against the anti-fXa activity.
47. The Japanese Pharmacopoeia Second fluid was prepared as follows. 0.2 mol/L sodium hydroxide solution (118 mL) was added to dihydrogenphosphonate potassium (6.80 g). To the mixture, water was added to make colorless clear liquid (1000 mL). The pH of this liquid was confirmed to be 6.70-6.90. Before use, the liquid was filtered by membrane filter.
48. The solubilities were determined by HPLC analysis. Ten millimolar of compound solution in DMSO (50 μl) was freeze-dried. To the residue the Japanese Pharmacopoeia Second fluid (250 μl, pH 6.8) was added, and the mixture was stirred by pipette operation. The mixture was stored under shade for 12 h. After filtration of the mixture, the filtrate was diluted by 20 times by adding aqueous DMSO solution (1:1 (v/v)) to obtain measurement sample solution. Five micromolar of compound solution in aqueous DMSO solution (1:1 (v/v)) and 100 μmol compound solution in aqueous DMSO solution (1:1 (v/v)) were prepared to make calibration curve. The measurement sample solution, 5 μmol solution, and 100 μmol solution were assayed using HPLC methodologies (Analytical Column: X Terra? MSC18 3.5 μm, 3.0× 30 mm, Waters; Mobile Phase: 10 mM ammonium acetate buffer (pH 4.5)/0.05% acetic acid in acetonitrile = 95:5-10:90 v/v; Wavelength: PDA 220-420 nm). The solubilities were analyzed using Millenium software program (Waters).
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50. m = -ln [(X/100)/5]/1.0 * 45 * 20.
51. 2O (5 μL), and 0.1 U/mL human fXa (10 μL). The reaction was started by the addition of 0.75 M S-2222 (40 μL). The reaction velocity and anti-fXa activity (inhibition %) were obtained as mentioned above.
52. Synthetic compound was administered orally to monkey (1 mg/kg) in aqueous solution. Blood samples were collected using Labospeed tubes (Toyo-kizai Inc.) at 0.5, 1, 2, 4, 8, and 24 h after oral dosing. Respective samples at each time points were collected in n = 3. Serum concentrations for synthetic compound were determined by LC-MS/MS using Sciex API 365 (Sciex Inc.) coupled with Alliance 2690 HPLC system (Waters Inc.). Compound was separated on a Symmetry C18 column (Waters Inc.). The quantitation limit was 7 ng/mL. Respective pharmacokinetic parameters were measured using Top Fit ver. 2.0 (Gustav Fischer Inc.).