Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A₂α Inhibitors

Abstract

This article describes the design, synthesis, and biological evaluation of new indole-based cytosolic phospholipase A2α (cPLA2α, a group IVA phospholipase A2) inhibitors. A screening-hit compound from our library, (E)-3-{4-[(4-chlorophenyl)thio]-3-nitrophenyl}acrylic acid (5), was used to design a class of 3-(1-aryl-1H-indol-5-yl)propanoic acids as new small molecule inhibitors. The resultant structure-activity relationships studied using the isolated enzyme and by cell-based assays revealed that the 1-(p-O-substituted)phenyl, 3-phenylethyl, and 5-propanoic acid groups on the indole core are essential for good inhibitory activity against cPLA2α. Optimization of the p-substituents on the N1 phenyl group led to the discovery of 56n (ASB14780), which was shown to be a potent inhibitor of cPLA2α via enzyme assay, cell-based assay, and guinea pig and human whole-blood assays. It displayed oral efficacy toward mice tetradecanoyl phorbol acetate-induced ear edema and guinea pig ovalbumin-induced asthma models.

ASB14780, an Orally Active Inhibitor of Group IVA Phospholipase A2, Is a Pharmacotherapeutic Candidate for Nonalcoholic Fatty Liver Disease

“…In addition, pentoxifylline, which acts as an anti-inflammatory agent by inhibiting tumor necrosis factor a production (Tilg, 2010), has been considered for the treatment of NASH (Zein et al, 2011). Similar to corticosteroids and pentoxifylline, ASB14780 prevented the development of NAFLD symptoms, such as fatty liver and hepatic fibrosis, probably through its activity as an inhibitor of IVA-PLA 2 (Tomoo et al, 2014).…”

“…Since none of these inhibitors is orally active, the prospect of using an IVA-PLA 2 inhibitor has been limited. However, we recently developed an indole derivative, ASB14780 (3-[1-(4-phenoxyphenyl)-3-(2-phenylethyl)-1H-indol-5-yl]propanoic acid 2-amino-2-(hydroxymethyl)propane-1,3-diol salt), as a specific inhibitor of IVA-PLA 2 (Tomoo et al, 2014). It has desirable bioavailability and oral efficacy, because it does not contain hydrophobic long alkyl chains (Tomoo et al, 2014).…”

“…However, we recently developed an indole derivative, ASB14780 (3-[1-(4-phenoxyphenyl)-3-(2-phenylethyl)-1H-indol-5-yl]propanoic acid 2-amino-2-(hydroxymethyl)propane-1,3-diol salt), as a specific inhibitor of IVA-PLA 2 (Tomoo et al, 2014). It has desirable bioavailability and oral efficacy, because it does not contain hydrophobic long alkyl chains (Tomoo et al, 2014). The specificity of ASB14780 has been demonstrated, and ASB14780 inhibited human IVA-PLA 2 with an IC 50 value of 20 nM, which was excellent compared with other known secreted phospholipase A 2 s (sPLA 2 s), such as sPLA 2 -IA (cobra venom), sPLA 2 -IIA (crotalus venom), sPLA 2 -III (bee venom), and sPLA 2 -IB (porcine pancreas), which have IC 50 values of ∼10 mM in vitro (Tomoo et al, 2014).…”

“…It has desirable bioavailability and oral efficacy, because it does not contain hydrophobic long alkyl chains (Tomoo et al, 2014). The specificity of ASB14780 has been demonstrated, and ASB14780 inhibited human IVA-PLA 2 with an IC 50 value of 20 nM, which was excellent compared with other known secreted phospholipase A 2 s (sPLA 2 s), such as sPLA 2 -IA (cobra venom), sPLA 2 -IIA (crotalus venom), sPLA 2 -III (bee venom), and sPLA 2 -IB (porcine pancreas), which have IC 50 values of ∼10 mM in vitro (Tomoo et al, 2014). Based on these findings about ASB14780, we examined its effects on the progression of fatty liver and hepatic fibrosis in mice.…”

Highly Potent 2-Oxoester Inhibitors of Cytosolic Phospholipase A2 (GIVA cPLA2)

“…7 Pharmacological inhibition of GIVA cPLA 2 by inhibitor 2 (Figure 1) blocked Streptococcus pneumoniae -induced polymorphonuclear cells transepithelial migration in vitro, suggesting that this enzyme plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection. 8 The daily administration of the indole-based inhibitor ASB14780 ( 3 , Figure 1), which had been developed by Tomoo and colleagues, 9 markedly ameliorated liver injury and hepatic fibrosis following 6 weeks of treatment with CCl 4 , indicating that a GIVA cPLA 2 inhibitor could be useful for the treatment of nonalcoholic fatty liver diseases, including fatty liver and hepatic fibrosis. 10 A few years ago, we presented new thiazolyl ketones as inhibitors of GIVA cPLA 2 and demonstrated the in vivo anti-inflammatory activity of inhibitor GK470 ( 4 , Figure 1) in a collagen-induced arthritis model.…”