title: Human glucagon receptor antagonists with thiazole cores. A novel series with superior pharmacokinetic properties.
abstract: The aim of the work presented here was to design and synthesize potent human glucagon receptor antagonists with improved pharmacokinetic (PK) properties for development of pharmaceuticals for the treatment of type 2 diabetes. We describe the preparation of compounds with cyclic cores (5-aminothiazoles), their binding affinities for the human glucagon and GIP receptors, as well as affinities for rat, mouse, pig, dog, and monkey glucagon receptors. Generally, the compounds had slightly less glucagon receptor affinity compared to compounds of the previous series, but this was compensated for by much improved PK profiles in both rats and dogs with high oral bioavailabilities and sustained high plasma exposures. The compounds generally showed species selectivity for glucagon receptor binding with poor affinities for the rat, mouse, rabbit, and pig receptors. However, dog and monkey glucagon receptor affinities seem to reflect the human situation. One compound of this series, 18, was tested intravenously in an anesthetized glucagon-challenged monkey model of hyperglucagonaemia and hyperglycaemia and was shown dose-dependently to decrease glycaemia. Further, high plasma exposures and a long plasma half-life (5.2 h) were obtained.
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark. pem@novonordisk.com
authors.forename: Peter
authors.initials: P
authors.lastname: Madsen
authors.forename: János T
authors.initials: JT
authors.lastname: Kodra
authors.forename: Carsten
authors.initials: C
authors.lastname: Behrens
authors.forename: Erica
authors.initials: E
authors.lastname: Nishimura
authors.forename: Claus B
authors.initials: CB
authors.lastname: Jeppesen
authors.forename: Lone
authors.initials: L
authors.lastname: Pridal
authors.forename: Birgitte
authors.initials: B
authors.lastname: Andersen
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Knudsen
authors.forename: Carmen
authors.initials: C
authors.lastname: Valcarce-Aspegren
authors.forename: Mette
authors.initials: M
authors.lastname: Guldbrandt
authors.forename: Inge T
authors.initials: IT
authors.lastname: Christensen
authors.forename: Anker S
authors.initials: AS
authors.lastname: Jørgensen
authors.forename: Lars
authors.initials: L
authors.lastname: Ynddal
authors.forename: Christian L
authors.initials: CL
authors.lastname: Brand
authors.forename: Morten Aa
authors.initials: MA
authors.lastname: Bagger
authors.forename: Jesper
authors.initials: J
authors.lastname: Lau
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013045:Species Specificity; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D018027:Receptors, Glucagon; D013844:Thiazoles