Optimization of Alkylidene Hydrazide Based Human Glucagon Receptor Antagonists. Discovery of the Highly Potent and Orally Available 3-Cyano-4-hydroxybenzoic Acid [1-(2,3,5,6-Tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide

Abstract

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-cyano-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-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC(50) = 2.3 nM, K(B) = 760 pM) and of the isolated rat receptor (IC(50) = 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.

Oxetanes as Versatile Elements in Drug Discovery and Synthesis

“…The introduction of steric hindrance often deflects chemical [69] or metabolic [70] liabilities from nearby functional groups. Especially in the case of metabolically unstable methylene groups as in a benzylic position, it is common practice to block metabolic attack by the introduction of a gem-dimethyl unit.…”

Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes

“…Several different classes of small molecule-based orally available Gcgr antagonists have been identified, including trisubstituted ureas, benzimidazole, alkylidene hydrazides, and ␤-alanine derivatives. These molecules were active following oral administration in dogs, rhesus monkeys, and nondiabetic and diabetic rodents (38,39,42,49). Furthermore, BAY27-995, a small-molecule Gcgr antagonist, successfully blocked exogenous glucagon-stimulated glucose production in human subjects (60).…”

Function and expression of somatostatin receptors of the endocrine pancreas

“…The immunoneutralization of the endogenous glucagon, administration of glucagon receptor antagonists, reduction of glucagon receptor expression or the deletion of glucagon receptors leads to a reduction of hyperglycemia in diabetic animal models (Brand et al, 1994;Liang et al, 2004;Gelling et al, 2003). Given the potential for SST to inhibit glucagon secretion it has been considered as adjunct therapy with insulin to treat diabetes (de Laszlo et al, 1999;Petersen and Sullivan 2001;Madsen et al, 2002).…”