Alpha-alkyl substituted pirinixic acid derivatives as potent dual agonists of the peroxisome proliferator activated receptor alpha and gamma

Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors, playing a pivotal role in energy homeostasis. Activators of the PPARalpha subtype are in widespread use for the treatment of hyperlipidemia, while activators of the PPARgamma subtype are in clinical use for the treatment of type-2 diabetes. Since both of these diseases are frequently associated, the combined treatment with one drug simultaneously activating PPARalpha and PPARgamma seems worthwhile. Starting with pirinixic acid, which is a moderately active dual PPARalpha/gamma agonist, we improved potency at the human PPARalpha and PPARgamma by substituting the alpha-position with an aliphatic chain. The maximal effect was achieved at a chain length of four and six carbons, respectively, leading to an activity induction by a factor of 36 for PPARalpha and 18 for PPARgamma, respectively.     

过氧化物酶体增殖物激活受体γ及其激动剂噻唑烷二酮类药物对骨骼成骨的影响及作用机制

过氧化物酶体增殖物激活受体γ(PPARγ)及配体是影响骨髓间充质干细胞分化与成熟的重要调控因子,可通过降低骨钙素、骨形成蛋白2等成骨细胞特异性成熟因子的表达,抑制成骨细胞的分化,亦可诱导成骨细胞的凋亡,最终导致骨丢失。目前普遍认为PPARγ参与了老年性骨质疏松、绝经后骨质疏松和继发性骨质疏松的发生、发展。PPARγ激动剂噻唑烷二酮类药物(TZDs)因其导致骨量降低、增加骨折发生率而备受争议,通过化学结构修饰将有可能避免这一不良反应发生。     

过氧化物增殖物活化受体γ辅激活因子1的生理作用及其与2型糖尿病的关系

过氧化物增殖物活化受体γ辅激活因子1（peroxisome prolifer atoractivated receptor γ coactivator-1,PGC-1）是一种辅激活因子,通过与核受体或非核受体转录因子结合,共同激活靶基因的转录与表达。PGC-1的靶基因是能量代谢,糖、脂代谢等生理过程的关键基因,因而对正常的能量平衡起着重要的调节作用。最近的研究表明PGC-1的遗传多态性与2型糖尿病的发生密切相关,有可能成为一个新的治疗靶点。     

Potential therapeutic role of peroxisome proliferator activated receptor-gamma agonists in psoriasis

Psoriasis is a chronic inflammatory condition affecting 1 - 3% of the world's population. Despite the availability of several agents, therapeutic options remain limited. With a better understanding of the pathophysiology of psoriasis, several potential therapeutic targets have been identified. Peroxisome proliferator activated receptors have been shown to play a role in cutaneous homeostasis. This review focuses on the potential therapeutic role of peroxisome proliferator activated receptor-gamma agonists in psoriasis and the possibility for the future prospects.     

Novel oxazole containing phenylpropane derivatives as peroxisome proliferator activated receptor agonists with hypolipidemic activity

alpha-Alkoxy arylpropanoic acids containing 2-phenyloxazole-4yl-alkyl moiety are found to be potent hypolipidemic agents. These compounds were potent activators of the peroxisome proliferator activated receptor gamma (PPARgamma), with moderate PPARalpha activity and known to cause adverse effects such as weight gain and edema, which are essentially attributed to PPARgamma activation. Although extensive work has been done on the phenylpropanoic acid class of compounds, other phenyl propane derivatives such as alcohols, amines, ethers etc. have not received much attention. In order to develop predominant PPARalpha agonists as hypolipidemic agents with minor chemical modifications on compound III, we have synthesised few (2S)-ethoxyphenylpropane derivatives containing a 2-phenyl-5-methyloxazole-4ylalkoxy moiety of the general formula IV and evaluated by PPARalpha and gamma transactivation assay in conjugation with in vivo studies in male Swiss albino mice model. Compounds 3c and 3d showed the desired predominant PPARalpha activity and excellent tryiglyceride reduction in vivo and were selected as lead compounds for further development as hypolipidemic agents.     

Design,synthesis, and evaluation of substituted phenylpropanoic acid derivatives as human peroxisome proliferator activated receptor activators. Discovery of potent and human peroxisome proliferator activated receptor alpha subtype-selective activators

Substituted phenylpropanoic acid derivatives were prepared as part of a search for subtype-selective human peroxisome proliferator activated receptor alpha (PPARalpha) activators. Structure-activity relationship studies indicated that the nature and the stereochemistry of the substituent at the alpha-position of the head part containing the carboxyl group, the distance between the carboxyl group and the central benzene ring, the linking group between the central benzene ring and the distal benzene ring, and the substituent at the distal hydrophobic tail part of the molecule all play key roles in determining the potency and selectivity of PPAR subtype transactivation. This study has led to the identification of potent and human PPARalpha selective optically active alpha-alkylphenylpropanoic acid derivatives, which will be useful not only as pharmacological tools to investigate the physiology and pathophysiology of PPARalpha but also as candidate drugs for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.     

Bradykinin B2 receptor as a potential therapeutic target

Kinins are peptide hormones that exert pathophysiological as well as pronounced beneficial physiological effects, mainly by stimulation of bradykinin (BK) B(2) receptors. Owing to the strong proinflammatory properties of kinins resulting from vasodilation, plasma extravasation, activation of mast cells, fibroblasts and macrophages, stimulation of sensory neurons, and the release of nitric oxide, prostaglandins, leukotrienes and cytokines, kinins are believed to play an important role in a variety of inflammatory diseases and pain. Beneficial effects of BK B(2) receptor antagonists in perennial rhinitis, asthma and brain edema have already been shown in clinical trials. Recently, the potential therapeutic utility of BK B(2) receptor antagonists has been extended by the discovery of orally active, nonpeptide BK B(2) receptor antagonists and the identification of novel indications for their use. On the other hand, kinins also have been identified as potent antihypertensive and organ-protective peptides. They have been shown to have vasodilatory, antihypertrophic, antiaggregatory and fibrinolytic effects due to the BK B(2) receptor-mediated release of the autacoids nitric oxide, prostacyclin and tissue plasminogen activator. A recent finding is that kinins are also involved in ischemic preconditioning. Orally active, nonpeptide BK B(2) receptor agonists as potential novel therapeutic agents in cardiovascular medicine have also been identified. In conclusion, interaction with the BK B(2) receptor by either its blockade or its stimulation offers promising therapeutic approaches. BK B(2) receptor antagonists may prove to be useful in the treatment of asthma, rhinitis, arthritis, colitis, pancreatitis, sepsis, edema, tissue injury, pain and possibly infections, hepatorenal syndrome, Alzheimer's disease and lung cancer. BK B(2) receptor agonists have potential in the treatment of cardiovascular diseases like hypertension, cardiac hypertrophy, restenosis and myocardial infarction and diabetic disorders.     

Androgen receptor as a therapeutic target

Androgens function as sex hormone primarily via activation of a single androgen receptor (AR, or NR3C4). AR is an important therapeutic target for the treatment of diseases such as hypogonadism and prostate cancer. AR ligands of different chemical structures and/or pharmacological properties are widely used for these therapeutic applications, and all of the AR ligands currently available for therapy modulate AR function via direct binding to the ligand-binding pocket (LBP) of the receptor. In the past ten years, our understanding of AR structure and molecular mechanism of action has progressed extensively, which has encouraged the rapid development of newer generation of AR ligands, particularly tissue-selective AR ligands. With improved tissue selectivity, future generations of AR ligands are expected to greatly expand the therapeutic applications of this class of drugs. This review will provide an overview of the common therapeutic applications of currently available AR ligands, and discussion of the major challenges as well as novel therapeutic strategies proposed for future drug development.     

Regulation of Octn2 transporter (SLC22A5) by peroxisome proliferator activated receptor alpha

The tissue distribution and disposition of carnitine, which plays an important role in the transport of long-chain fatty acids across the mitochondrial inner membrane for beta-oxidation, are well controlled by carnitine transporter organic cation/carnitine transporter 2 (OCTN2). Since little information is available on regulation of the expression of the OCTN2 gene, we examined the factors that affect the expression level of rat Octn2 (rOctn2), focusing on nuclear receptor peroxisome proliferator activated receptor alpha (PPARalpha), which regulates expression of genes associated with beta-oxidation of fatty acids. mRNA of rOctn2 was induced by the PPARalpha ligand fenofibrate in primary-cultured rat hepatocytes. Further, the PPARalpha ligand Wy14643 increased the expression of Octn2 in wild-type mice, but not in PPARalpha knockout mice. Analysis of the rOctn2 promoter region suggested the presence of putative cis elements of PPARalpha. Wistar rats treated with intraperitoneal fenofibrate administration showed increased expression of rOctn2 mRNA in liver, and uptake of [3H]carnitine by freshly isolated hepatocytes derived from those rats was also increased. In conclusion, our results indicate that the nuclear receptor PPARalpha directly up-regulates the expression of rOctn2 and increases the hepatic uptake of carnitine via rOctn2.     

Mouse hepatocyte response to peroxisome proliferators: dependency on hepatic nonparenchymal cells and peroxisome proliferator activated receptor alpha (PPARalpha)

Peroxisome proliferators (PPs) are rodent nongenotoxic hepatocarcinogens that induce peroxisome proliferation and DNA synthesis, and suppress apoptosis in rodent hepatocytes. PPs act through the PP-activated receptor alpha (PPARalpha); tumour necrosis factor alpha (TNFalpha) and hepatic nonparenchymal cells (NPCs), the major source of TNF alpha in the liver, have also been implicated in mediating the rodent hepatic response to PPs. Here we investigate the interaction between PPARalpha and NPCs in regulating the response to PPs. Using normal hepatocyte cultures containing around 20% NPCs, the PP nafenopin (50 microM) induced DNA synthesis and suppressed transforming growth factor beta1-induced apoptosis. However, when the NPCs were removed by differential centrifugation, nafenopin did not induce DNA synthesis or suppress apoptosis in the pure hepatocytes. Reconstitution of the normal hepatocyte cultures by mixing together the pure hepatocytes and the previously separated NPCs in the same proportions as the original cell preparation (17.7+/-8.7% NPCs) restored the response to nafenopin. Interestingly, nafenopin was still able to induce beta-oxidation in the pure hepatocyte cultures, consistent with NPCs being required for PP-induced growth but not for peroxisome proliferation. Next, we evaluated the role of PPARalpha in the hepatocyte dependency upon NPCs. Interestingly, NPCs isolated from PPARalpha-null mice, like those isolated from the wild-type NPCs, restored the hepatocyte response to nafenopin. However, as expected, PPARalpha-null hepatocytes remained non-responsive to PPs, irrespective of the genotype of the added NPCs. These data support a role for NPCs in facilitating a response of hepatocytes to PPs that is ultimately dependent on the presence of PPARalpha in the hepatocyte.     

The P2X7 receptor as a therapeutic target

Background: The P2X7 receptor is present in a variety of cell types involved in pain, inflammatory processes and neurodegenerative conditions, thus it may be an appealing target for pharmacological intervention. The extensive use of high-throughput screening (HTS) followed by a hit-to-lead (HtL) program, has prompted a number of firms to identify highly selective and metabolically stable small-molecules possessing activity for both the rat and human P2X₇ receptor, which provide a novel therapeutic approach to the treatment of pain as well as neurodegenerative and inflammatory disorders. Objective: To describe the current status of and potential for development of P2X₇ receptor-antagonists. Methods: A literature review. Results/conclusions: We describe the recent discoveries of novel P2X₇ receptor-selective antagonists, along with their biological activity and therapeutic potential.     

Glucagon as a target for the treatment of Type 2 diabetes

Glucagon is the key counter-regulatory hormone that opposes the action of insulin. In states of relative hypoglycaemia, glucagon acts to increase blood glucose by stimulating hepatic glycogen breakdown and gluconeogenesis to achieve euglycaemia. Type 2 diabetes is characterised by inappropriate regulation of hepatic glucose production, which is due, at least in part, to an imbalance in the bihormonal relationship between plasma levels of glucagon and insulin. The glucose-lowering effects of glucagon peptide antagonists and antiglucagon neutralising antibodies first demonstrated the potential of glucagon receptor (GCGR) antagonism as a treatment for hyperglycaemia. In recent years, the development of GCGR antisense oligonucleotides and small molecular weight GCGR antagonists have been pursued as possible therapeu-tic agents to target glucagon action as a treatment for Type 2 diabe-tes.     

Glucagon as a target for the treatment of Type 2 diabetes

Glucagon is the key counter-regulatory hormone that opposes the action of insulin. In states of relative hypoglycaemia, glucagon acts to increase blood glucose by stimulating hepatic glycogen breakdown and gluconeogenesis to achieve euglycaemia. Type 2 diabetes is characterised by inappropriate regulation of hepatic glucose production, which is due, at least in part, to an imbalance in the bihormonal relationship between plasma levels of glucagon and insulin. The glucose-lowering effects of glucagon peptide antagonists and antiglucagon neutralising antibodies first demonstrated the potential of glucagon receptor (GCGR) antagonism as a treatment for hyperglycaemia. In recent years, the development of GCGR antisense oligonucleotides and small molecular weight GCGR antagonists have been pursued as possible therapeutic agents to target glucagon action as a treatment for Type 2 diabetes.