Acyliminothiadiazoline derivatives: New, highly potent, and orally active angiotensin II receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 13, 1996, Pages 1469-1474

  Hirata, Terukage ^a   Nomiyama, Jun ^a   Sakae, Nobuya ^a   Nishimura, Kouji ^a   Yokomoto, Masaharu ^a   Inoue, Satoshi ^a   Tamura, Koichi ^a   Okuhira, Masayasu ^a   Amano, Hirotaka ^a   Nagao, Yoshimitsu ^b  

^a WAKUNAGA PHARMACEUTICAL CO LTD   (Japan)

^b UNIVERSITY OF TOKUSHIMA   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ANGIOTENSIN RECEPTOR ANTAGONIST; LOSARTAN; LOSARTAN POTASSIUM; THIADIAZOLE DERIVATIVE;

ANTIHYPERTENSIVE ACTIVITY; ARTICLE; CONGESTIVE HEART FAILURE; DRUG ANTAGONISM; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; ENZYME INHIBITION; NONHUMAN; REACTION ANALYSIS; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; RENOVASCULAR HYPERTENSION;

CANIS FAMILIARIS;

EID: 0030576325     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(96)00250-8     Document Type: Article

References (18)

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8. (6) In general, alkylation of 2-acylamido-1,3,4-thiadiazoles except for 2-trifluoroacetamido derivatives 3 gives a mixture of the endo N- and exo N-alkylated products. See, Hirata, T.; Shiro, M.; Nagao, Y. Heterocycles accepted for publication.
9. 2, C : 51.97, H : 3.66, N : 16.97, Found, C : 51.90, H : 3.70, N : 16.97.
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11. (9) The binding assay was peformed by the method described in ref. 9. Robertson, M. J.; Barnes, J. C.; Drew, G. M.; Clark, K. L.; Marshall, F. H.; Michel, A.; Middlemiss, D.; Ross, B. C.; Scopes, D.; Dowle, M. D. Br. J. Pharmacol. 1992, 107, 1173.
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15. (11) The structure-activity relationships at the 5'-position of thiadiazoline ring were also investigated. The derivatives having an ethyl substituent were found to exhibit the highest binding affinity.
16. (12) Protocol for in vivo testing in conscious rats: Male Sprague-Dawley rats aged 8-9 weeks and weighing 250-350 g (Charles River Laboratories) were anesthetized with pentobarbital (40 mg/kg, ip), and the left femoral artery and vein were cannulated. The femoral artery catheter was connected to a pressure transducer (TP400T, Nihon Kohden, Tokyo Japan) coupled to a polygraph monitor mean arterial blood pressure. AII (100 ng/kg) was injected three times in the femoral vein to establish the control response. Test compounds were then administered orally at a constant volume of 5 ml/kg. Thereafter, AII was injected repeatedly at given times. The pressor response to AII at each dose of the test compounds was compared with that obtained for the pretreatment control.
17. (13) Protocol for in vivo testing in RHRs: Male Sprague-Dawley rats aged 6 weeks and weighing 250-350 g (Charles River Laboratories) were anesthetized with pentobarbital (40 mg/kg, ip). The left kideny artery was constricted with a silver clip (internal diameter 0.43 mm) and the right kidney was left intact. 4-7 weeks after the constriction, the animals were anesthetized with pentobarbital, and the left femoral artery was cannulated. The rats were permitted to recover overnight from anesthesia and allowed regular rat chow and water ad libitum. The experiments were started the next day. Their blood pressure was measured as described in ref. 12. The rats with mean arterial pressures of 160 to 190 mmHg were used. Test compounds were then administered orally (po) at a constant volume 5 ml/kg.
18. (14) The oral bioavailability of 1g in fasted beagle dogs was calculated as AUCpo/AUCiv x100. Serum concentrations of 1g after a single oral or intravenous administration (3 mg/kg) were determined by reverse phase high-performance liquid chromatography.