Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-eyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylenelhydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC50 = 2.3 nM, K-B = 760 pM) and of the isolated rat receptor IC50 = 430 pM, K-B = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K-i = 14 nM). This compound was orally available in dogs (F-po = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.

High throughput screening of our small molecule combinatorial library identified a class of benzoylnaphthalenehydrazones with modest affinity for the human glucagon receptor. Optimization of this initial hit through a series of targeted libraries and traditional medicinal chemistry led to ligands with nanomolar affinities. Pharmacological evaluation demonstrated that these ligands were competitive glucagon receptor antagonists. Intravenous administration of a representative benzoylnaphthalenehydrazone into rats attenuated glucagon-stimulated glucose levels.

On the basis of pharmacological observations, neuropeptide Y (NPY) has been implicated to be involved in numerous physiological functions. Preliminary results suggest a wide therapeutic utility for NPY antagonists in disorders such as anxiety, appetite stimulation, obesity, alcohol intake, hypertension, and regulation of coronary tone. This review will focus on patent applications describing non-peptidic NPY ligands published over the last ten years. Primary publications will be incorporated where appropriate.