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.

Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD‐6972 in healthy subjects and subjects with type 2 diabetes mellitus

“…Animal models of T2DM have demonstrated the utility of inhibiting glucagon action for treating T2DM . Glucagon receptor (GCGR) neutralizing antibodies, antisense oligonucleotides and/or peptide and small molecule glucagon receptor antagonists (GRAs) have been shown to significantly reduce blood glucose levels and improve glucose tolerance in various rodent obesity and/or diabetes models . In T2DM patients, small molecule GRAs suppress fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels .…”

Significance of Thiazole-based Heterocycles for Bioactive Systems

“…al. [99] explained the thiazole containing scaffold being potent human glucagon receptor antagonists with enhanced pharmacokinetic (PK) properties for expansion of pharmaceuticals for the medication of type-2 diabetes. The syntheses of compounds with cyclic moieties (5-aminothiazoles), their binding affinities for the human glucagon and GIP receptors, as well as affinities for mouse, pig, rat, dog, and monkey glucagon receptors.…”

Chapter 15. Glucagon Receptor Antagonists in Development

“…76 As an extension of their initial efforts with urea-based b-alanine benzamide hGCGR antagonists, Madsen and co-workers also probed heteroaromatic replacements for the urea functionality. 77,78 Their efforts afforded a series of potent and selective hGCGR antagonists which contained an aminothiazole 5 58%, t 1/2 5 228 min, C max 5 2100 ng/mL, T max 5 85 min, Cl 5 1 mL/ min?kg; PK dog: F po 5 141%, t 1/2 5 104 min, C max 51253 ng/mL, T max 5 90 min, Cl 5 2.23 mL/min?kg). Additionally, compound 15.69 was shown to inhibit glucose production in primary human hepatocytes (IC 50 5 6700 nM).…”