Metabolism investigation leading to novel drug design 2: Orally active prostacyclin mimetics. Part 5

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 17, 2006, Pages 4475-4478

  Takamura, Fujiko ^a   Tanaka, Akira ^a   Takasugi, Hisashi ^a   Taniguchi, Kiyoshi ^a   Nishio, Mie ^a   Seki, Jiro ^a   Hattori, Kouji ^a  

^a ASTELLAS PHARMA INC   (Japan)

Author keywords

FK788; Metabolism; PG; PGI2; Prostacyclin

Indexed keywords

DIPHENYLCARBAMOYL DERIVATIVE; FK 788; PROSTACYCLIN DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG METABOLISM; DRUG SCREENING; DRUG STABILITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; NONHUMAN; RAT;

ADMINISTRATION, ORAL; ANIMALS; BIOMIMETICS; DISEASE MODELS, ANIMAL; DRUG DESIGN; EPOPROSTENOL; HUMANS; LIVER; MICROSOMES; MOLECULAR STRUCTURE; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33746206240     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.06.033     Document Type: Article

References (11)

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2. *BP), where Qh and BP, respectively, are liver blood flow in humans (1500 mL/min/70 kg) and blood-to-plasma ratio of FK788 (0.57).
3. Glucuronidation of FK788 was not observed in rat excrement after intravenous administration of FK788, which is explained by being stable towards glucuronidation in vitro.
4. 14C-FK788 (10 μmol/L) was incubated at 37 °C with rat and human liver microsomes (1 mg protein/mL) in the presence of a NADPH-generating system. Incubation mixtures were analyzed by radio-HPLC and the concentrations of formed metabolites were determined.
5. FK788 was incubated at 37 °C with rat liver microsomes in the presence of a NADPH-generating system. M-2, M-4 and M-5 in incubation mixtures were isolated by HPLC and their chemical structures were determined by LC/MS/MS and NMR analysis.
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11. The compounds 2 and 7c were orally administered to rats 15-30 min prior to treatment with d-GalN (300 mg/kg)/LPS (0.32 μg/kg), and after 24 h, the blood was collected with a syringe from the abdominal artery. The separated plasma samples were examined for ALT levels by auto-analyzer.