Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists

Abstract

The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ≤ 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels.

Keywords: GLP-1 secretion; GPR39 agonists; GPR39 receptor; Zn2+-sensing receptor; antidiabetic treatment; insulin secretion; β-cell protection.

Figure 1

Discovery of 2-pyridylpyrimidines as GPR39 agonists.

Scheme 1. Synthesis of 3

Reagents and conditions: (a) MsCl, pyridine, 0 °C, 80% yield; (b) LiAlH₄, THF, 0 °C, 68% yield; (c) 2,4-dichloro-6-(pyridin-2-yl)pyrimidine, MeCN, triethylamine 60 °C, chromatographic separation on silica gel, 70% yield; (d) 15% MeNH₂ in EtOH, 130 °C, microwave heating, 87% yield.

Figure 2

Induction of a PD Marker, active GLP-1, for compounds 21 and 3.