Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
Cyclic Pentapeptide Endothelin A Receptor Antagonists with Attenuated in Vivo Clearance
Takehiro FUKAMIKenji NIIYAMAYuuka AMANOAkihiro HISAKANaoko FUJINOYoshio SAWASAKIMasaki IHARAKiyofumi ISHIKAWA
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1996 Volume 44 Issue 3 Pages 609-614

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Abstract

A series of analogues of BQ-123 (1), a potent cyclic pentapeptide endothelin A receptor antagonist, with amino acids linked to the side-chain of the Pro residue via an ester linkage was synthesized. All analogues synthesized exhibited potent endothelin A receptor binding affinity similar to that of 1. Of the synthesized analogues, the Lys, Arg and Nα, Nε-dimethyllysine analogues, 9d-f, exhibited about a three-fold attenuation of in vivo clearance compared with 1. In rats, these analogues exhibited a 3-fold-higher plasma concentration and a longer retention time in plasma as compared with those of 1. The attenuated in vivo clearance was thought to be a consequence of decreased extraction of the compounds from the blood via the hepatic anion transport system, which efficiently extracts 1 from the blood.

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© The Pharmaceutical Society of Japan
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