title: Cyclic pentapeptide endothelin A receptor antagonists with attenuated in vivo clearance.
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 N alpha,N epsilon-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.
authors.affiliation: Drug Discovery Research Laboratories, Banyu Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fukami
authors.forename: K
authors.initials: K
authors.lastname: Niiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Amano
authors.forename: A
authors.initials: A
authors.lastname: Hisaka
authors.forename: N
authors.initials: N
authors.lastname: Fujino
authors.forename: Y
authors.initials: Y
authors.lastname: Sawasaki
authors.forename: M
authors.initials: M
authors.lastname: Ihara
authors.forename: K
authors.initials: K
authors.lastname: Ishikawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D065128:Endothelin Receptor Antagonists; D006868:Hydrolysis; D008297:Male; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013552:Swine
chemical_list: D001798:Blood Proteins; D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)