Pharmacological Profiles of a Highly Potent and Long-Acting Angiotensin II Receptor Antagonist, Fimasartan, in Rats and Dogs after Oral Administration
| Autor: | Hee-Soo Han, Kyung-Tae Lee, Yong Ha Chi, Soo Heui Paik, Joo Han Lee |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Administration Oral Tetrazoles Pharmaceutical Science Blood Pressure Angiotensin II receptor antagonist 030204 cardiovascular system & hematology Pharmacology Rats Sprague-Dawley Angiotensin Receptor Antagonists 03 medical and health sciences Dogs 0302 clinical medicine Furosemide Oral administration Rats Inbred SHR Internal medicine Renin–angiotensin system medicine Animals Humans Fimasartan Angiotensin II receptor type 1 Chemistry Biphenyl Compounds General Medicine Angiotensin II Rats Candesartan HEK293 Cells Pyrimidines 030104 developmental biology Endocrinology Losartan Rabbits medicine.drug |
| Zdroj: | Biological & Pharmaceutical Bulletin. 40:992-1001 |
| ISSN: | 1347-5215 0918-6158 |
| DOI: | 10.1248/bpb.b16-00987 |
| Popis: | The pharmacological profile of fimasartan, [2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new non-peptide angiotensin type 1 (AT1)-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, fimasartan showed slow dissociation and irreversible binding to AT1 subtype receptors in membrane fractions of HEK-293 cells with a Kd of 0.03 nM and a T1/2 of 63.7 min. The inhibitory effect of fimasartan on angiotensin II (Ang II)-induced contraction persisted longer after washout than that of losartan or candesartan. In conscious rats, a single dose of fimasartan (0.3, 1, or 3 mg/kg; per os (p.o.)) dose-dependently antagonized Ang II-induced pressor responses. Both orally administrated fimasartan and losartan dose-dependently decreased mean arterial pressure in furosemide-treated rats and dogs, and fimasartan administered orally at 1, 3, or 10 mg/kg reduced blood pressure in conscious spontaneously hypertensive rats. Taken together, these findings indicate that fimasartan has potent and sustained binding affinity at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in various conscious rats and dogs models after its oral administration. |
| Databáze: | OpenAIRE |
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