A Second Generation Prostanoid Receptor Antagonist Acting at Multiple Receptor Subtypes

Abstract

It has previously been reported that a prototypical compound (AGN 211377), which blocks pro-inflammatory prostanoid receptors (DP 1 , DP 2 , EP 1 , EP 4, FP, TP) and leaves open IP and EP 2 receptors so that their anti-inflammatory properties could be exerted, produced superior inhibitory effects on cytokine release from human macrophages compared to cyclooxygenase (COX) inhibitors. This favorable activity profile translated into animal studies, with AGN 211377 exceeding the level of inhibition afforded by COX inhibition. AGN 211377 was not, however, a practical drug candidate, having poor bioavailability and cost of goods concerns. Compound 1 (designated AGN 225660) represents a second-generation compound with an entirely different "druggable" core structure. Such a dramatic change in chemical scaffold created uncertainty with respect to matching the effects of AGN 211377. AGN 225660 inhibited RANTES, IL-8, and MCP-1 secretion by at least 50%, from TNFα activated human macrophages. Although AGN 225660 reduced TNFα-evoked MCP-1 release from human monocyte-derived macrophages, it increased LPS-induced MCP-1 secretion (up to 2-fold) from human monocyte-derived dendritic cells. However, AGN 225660 inhibited the release of IL12p 70 and IL-23 from human monocyte-derived dendritic cells stimulated by LPS by more than 70%. This effect of AGN 225660 was reproduced in part by the prototype compound AGN 211377 and a combination of selective DP 1 , EP 1 , EP 4 , FP, and TP antagonists. These findings suggest important effects on T cell skewing and disease modification by this class of therapeutic agents. AGN 225660 exhibited good ocular bioavailability and was active in reducing ocular inflammation associated with phacoemulsification surgery, LPS, and arachidonic acid induced uveitis.

Compounds targeting multiple prostanoid receptors

“…AGN 211377 had an appealing poly-pharmacological activity profile but it has a chemical backbone that closely resembles that of naturally occurring eicosanoids [1,6], which resulted in unsatisfactory oral and ocular bioavailability [8]. This is a problem frequently addressed by medicinal chemistry and the solution lay in a dramatically different, non-eicosanoid chemical scaffold [8]. This class of compounds is represented by AGN 225660, which has a pyrazole based scaffold [8].…”

“…This is a problem frequently addressed by medicinal chemistry and the solution lay in a dramatically different, non-eicosanoid chemical scaffold [8]. This class of compounds is represented by AGN 225660, which has a pyrazole based scaffold [8]. This compound retained all the anti-inflammatory properties of AGN 211377 and, in addition, was discovered to inhibit the release of IL-23 and IL-12p70 from human monocyte-derived dendritic cells [8].…”

“…This class of compounds is represented by AGN 225660, which has a pyrazole based scaffold [8]. This compound retained all the anti-inflammatory properties of AGN 211377 and, in addition, was discovered to inhibit the release of IL-23 and IL-12p70 from human monocyte-derived dendritic cells [8].…”

“…AGN 211377 and AGN 225660 were both active in models of ocular inflammation and clearly exceeded the activity of cyclo-oxygenase inhibitors and antagonists selective for a single prostanoid receptor [7,8]. The prognosis would arguably be favorable for activity in other models of inflammation, such as rheumatoid and osteoarthritis.…”

“…Nevertheless, those receptors involved in stimulating mast cells [10][11][12], eosinophils [13,14], airway constriction and airway smooth muscle hypertrophy [15,16], cough [17,18], and mucus hypersecretion [19] are known. The EP 2 receptor is known to physiologically oppose the activation of mast cells, eosinpohils, and cytokine release from monocyte-derived macrophages and dendritic cells, all of which has been extensively documented [6,8,[20][21][22][23][24][25][26][27]. The advantages of blocking multiple prostanoid receptors versus selective antagonism of a single prostanoid receptor can be envisioned by the diagram Figure 4.…”