Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors. In experiments using Gpr40- and Gpr84-knockout mice in models of kidney fibrosis (unilateral ureteral obstruction, long-term post-acute ischemic injury, and adenine-induced chronic kidney disease), we found that GPR40 is protective and GPR84 is deleterious in these diseases. Moreover, through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in many injury contexts, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models. Therefore, GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related diseases.

Non-alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is associated with metabolic dysregulation. Although G protein-coupled receptor 84 (GPR84) has been associated with inflammation, its role in metabolic regulation remains elusive. The aim of our study was to evaluate the potential of PBI-4547 for the treatment of NAFLD and to validate the role of its main target receptor, GPR84. We report that PBI-4547 is a fatty acid mimetic, acting concomitantly as a GPR84 antagonist and GPR40/GPR120 agonist. In a mouse model of diet-induced obesity, PBI-4547 treatment improved metabolic dysregulation, reduced hepatic steatosis, ballooning and NAFLD score. PBI-4547 stimulated fatty acid oxidation and induced gene expression of mitochondrial uncoupling proteins in the liver. Liver metabolomics revealed that PBI-4547 improved metabolic dysregulation induced by a high-fat diet regimen. In Gpr84 −/− mice, PBI-4547 treatment failed to improve various key NAFLD-associated parameters, as was observed in wildtype littermates. Taken together, these results highlight a detrimental role for the GPR84 receptor in the context of meta-inflammation and suggest that GPR84 antagonism via PBI-4547 may reflect a novel treatment approach for NAFLD and its related complications. Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent chronic liver disease worldwide and is among the top three causes of liver transplantation in the US. NAFLD represents the pathological hepatic manifestation of metabolic dysregulation including fatty acid (FA) metabolism, not caused by excessive alcohol consumption, pro-steatogenic drugs or hereditary disorders and is defined by the presence of steatosis in the liver, due to triglyceride accumulation in hepatocytes (> 5% of total fat content) 1. Pathological signs range from steatosis to non-alcoholic steatohepatitis (NASH), which represents the most severe condition. Although the precise molecular mechanisms underlying the progression from simple steatosis to NASH remain elusive, several key risk factors are known to be intimately involved including inflammation, diet and infectious agents. The most important risk factor for NAFLD/NASH is type-II diabetes mellitus and remains a strong predictor for development of adverse clinical outcomes including advanced liver fibrosis and death. Other aggravating factors, such

It is known that peptides corresponding to the C-terminus of the small subunit of herpes simplex virus type 1 and 2 ribonucleotide reductase can inhibit enzymatic activity by preventing the association of the enzyme's two subunits. In a quest for smaller, more potent inhibitors, we have conducted a structure activity investigation based on the pentapeptide H-Val-Val-Asn-Asp-Leu-OH. Potency increases of up to 4000 times (IC50 0.18 microM) have been achieved in an enzymatic assay by a combination of modifying the N-terminal valine to a diethylacetyl group, adding a methyl group to the beta-carbon of the adjacent valine, dialkylating the asparagine side-chain nitrogen and dimethylating the beta-carbon of the aspartic acid residue. In addition the relative contribution of various inhibitor functionalities to inhibitor potency has been investigated.

In recent years much attention has been focused on the synthesis of ketomethylene isosteres and their use in biologically active peptides. 1 In the course of our studies on peptidomimetic inhibitors we needed a facile synthesis of aspartic acid ketomethylene dipeptide isosteres (AAΨ[COCH 2 ]Asp). Here we report a practical synthesis of this type of isostere that features a diastereoselective Michael addition and provides suitably protected functionalities for subsequent transformations. 2 The synthesis, outlined in Scheme 1, began with the N-Boc protected amino acid methyl esters 1a-e which were converted into the ketophosphonates 2a-e in good yield by treatment with 8 equiv of lithium dimethyl methylphosphonate in THF at -78 °C. The trans-Michael acceptors 3a,b were prepared by treating the ketophosphonates 2a,b with 1.05 equiv of benzyl glyoxylate 3 in the presence of 2.0 equiv of triethylamine in acetonitrile at room temperature. However, we found that the above reaction conditions were not suitable for the preparation of Michael acceptors bearing smaller alkyl groups 3c-e. We observed racemization 4 and formation of the corresponding rearranged products 6. 5 We believed that products 6 were formed via a basedcatalyzed 1,5-hydrogen shift as shown in Scheme 2. These problems were overcome by replacing triethylamine by a weaker base, N-methylmorpholine, and by lowering the reaction temperature to 0 °C. These modifications necessitated longer reaction times and since these Michael acceptors were somewhat unstable, we found that the use of dichloromethane and molecular sieves reduced the quantity of minor byproducts. It should be noted that the use of N-methylmorpholine in the Wadsworth-Emmons reaction of phosphonates 2a,b gave a substantial amount of the cis isomer. We found that the cis isomer was not a suitable substrate for the subsequent reaction.The first step in the stereoselective introduction of the tert-butyl acetate side chain involved the conjugate addition of the sodium salt of allyl tert-butyl malonate 6 to 3a-e to give the adducts 4a-e in >90% yields. However, at this stage the unsymmetrical malonate moiety made the assessment of the diastereoisomeric purity of 4a-e difficult. We thus assessed the degree of (1) For pertinent references on this topic see:

Macrocyclic Substrate-Based β-Strand Mimics. -(GOUDREAU, N.; BROCHU, C.; CAMERON, D. R.; DUCEPPE, J.-S.; FAUCHER, A.-M.; FERLAND, J.-M.; GRAND-MAITRE, C.; POIRIER, M.; SIMONEAU, B.; TSANTRIZOS*, Y. S.; J.