title: Development of an efficient strategy for the synthesis of the ETB receptor antagonist BQ-788 and some related analogues.
abstract: BQ-788 [N-cis-2,6-dimethylpiperidine-1-carbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine sodium salt] is a very potent and selective ETB receptor antagonist. The formation of the highly hindered trisubstituted urea functionality in the peptide chain and the carbamination on the indole nitrogen of the tryptophan side chain are major challenges in the synthesis of this particular antagonist. Furthermore, the high cost of the unnatural amino acids in the sequence of BQ-788 and its reported synthesis render this pseudopeptide very expensive to produce. In order to improve the yield and to reduce the number of steps compared to previous reported syntheses, we developed an efficient strategy involving a novel one-pot procedure for the synthesis of a highly hindered trisubstituted urea. Under very mild conditions, the urea was obtained by using triphosgene and sodium iodide. This strategy allowed us to synthesize BQ-788 in seven steps with an overall yield of 53%. We also generalized the use of this powerful methodology by creating some new structural analogues of the cis-2,6-dimethylpiperidine moiety by replacing it with other bulky secondary amines. We evaluated the antagonist properties of those three new analogues of BQ-788 in two bioassays in vitro. These new antagonists were less potent than BQ-788 in an ETB rich preparation and inactive in an ETA rich preparation.
authors.affiliation: Department of Pharmacology, IPS, Medical School, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brosseau
authors.forename: Pedro
authors.initials: P
authors.lastname: D'Orléans-Juste
authors.forename: Witold A
authors.initials: WA
authors.lastname: Neugebauer
mesh_terms: D000818:Animals; D002343:Carotid Artery, Internal / Q000187:drug effects; D065131:Endothelin B Receptor Antagonists; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects; D011817:Rabbits; D044023:Receptor, Endothelin B / Q000819:agonists
chemical_list: D065131:Endothelin B Receptor Antagonists; D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; C086539:BQ 788