RESUMO
Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.
Assuntos
Anti-Hipertensivos/farmacologia , Inibidores Enzimáticos/farmacologia , Éteres Fenílicos/farmacologia , Renina/antagonistas & inibidores , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Disponibilidade Biológica , Cristalografia por Raios X , Citocromo P-450 CYP3A/sangue , Inibidores do Citocromo P-450 CYP3A , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hipertensão/tratamento farmacológico , Modelos Moleculares , Conformação Molecular , Éteres Fenílicos/síntese química , Éteres Fenílicos/química , Ratos , Ratos Transgênicos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/isolamento & purificação , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11ß-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/farmacologia , Inibidores Enzimáticos/farmacologia , Adamantano/química , Animais , Descoberta de Drogas , Inibidores Enzimáticos/química , Modelos Moleculares , RatosRESUMO
Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.
Assuntos
Aminas/química , Carbamatos/química , Inibidores Enzimáticos/química , Piperidinas/química , Renina/antagonistas & inibidores , Administração Oral , Aminas/síntese química , Aminas/farmacocinética , Animais , Sítios de Ligação , Pressão Sanguínea/efeitos dos fármacos , Carbamatos/síntese química , Carbamatos/farmacocinética , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Humanos , Piperidinas/síntese química , Piperidinas/farmacocinética , Ratos , Ratos Transgênicos , Renina/sangue , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Desenho de Fármacos , Ureia/administração & dosagem , Ureia/farmacocinética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Sítios de Ligação/fisiologia , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Humanos , Macaca fascicularis , Camundongos , Ratos , Relação Estrutura-Atividade , Ureia/análogos & derivadosRESUMO
Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
Assuntos
Anti-Hipertensivos/química , Metilaminas/química , Renina/antagonistas & inibidores , Administração Oral , Sequência de Aminoácidos , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Pressão Sanguínea , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Metilaminas/síntese química , Metilaminas/farmacocinética , Ratos , Ratos Transgênicos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
Inhibition of renin has been shown to be successful in managing hypertension and maintaining cardiac health. Canine models have played a key role in preclinical assessment of renin inhibitors. Here we report the cloning of canine prorenin gene. The amino acid sequence of mature canine renin was approximately 70% identical to that of human renin. The full-length prorenin was expressed in HEK 293 cells, purified and converted to its active form by trypsin-mediated cleavage of the 43 residue propeptide. The mature enzyme was characterized by steady-state kinetics using a peptide corresponding to the canine angiotensinogen sequence, Ac-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser-OH (cleavage between Leu(10)-Leu(11)). The reaction followed Michaelis-Menten kinetics with a K(M) of 120 microM and a second-order rate constant (k(cat)/K(M)) of 1.7 x 10(5) M(-)(1)s(-)(1). The enzyme was inhibited by various human renin inhibitors, but at reduced potency compared to the human renin. The basis of the species specificity was investigated by mutagenesis. Based on primary sequence and structural alignments, three mutants were prepared (G149S-S150T, V286L, G149S-S150T-V286L). Each mutant yielded catalytically active enzymes with lower specific activities than native canine renin. V286L had the greatest effect on substrate specificity, while G149S, S150T mutations produced enzymes with inhibitor profiles similar to human renin.
Assuntos
Renina/genética , Renina/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Clonagem Molecular , Cães , Inibidores Enzimáticos/farmacologia , Precursores Enzimáticos/isolamento & purificação , Precursores Enzimáticos/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Cinética , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Renina/química , Homologia de Sequência de AminoácidosRESUMO
A sensitive optical detector is presented based on a deeply depleted graphene-insulator-semiconducting (D2GIS) junction, which offers the possibility of simultaneously leveraging the advantages of both charge integration and localized amplification. Direct read-out and built-in amplification are accomplished via photogating of a graphene field-effect transistor (GFET) by carriers generated within a deeply depleted low-doped silicon substrate. Analogous to a depleted metal-oxide-semiconducting junction, photo-generated charge collects in the potential well that forms at the semiconductor/insulator interface and induces charges of opposite polarity within the graphene film modifying its conductivity. This device enables simultaneous photo-induced charge integration with continuous "on detector" readout through use of graphene. The resulting devices exhibit responsivities as high as 2,500 A/W (25,000 S/W) for visible wavelengths and a dynamic range of 30 dB. As both the graphene and device principles are transferrable to arbitrary semiconductor absorbers, D2GIS devices offer a high-performance paradigm for imaging across the electromagnetic spectrum.
RESUMO
Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAS) which controls blood pressure and volume. The biological function of renin is to cleave the N-terminus of angiotensinogen releasing the decapeptide, angiotensin I (ANGI). Subsequently, angiotensin I is further processed by the angiotensin converting enzyme (ACE) to produce angiotensin II (ANGII). The RAS cascade is a major target for the clinical management of hypertension. Current clinical treatments include angiotensin converting enzyme inhibitors (ACEi) and ANGII receptor blockers (ARBs). As the rate-limiting enzyme in ANGII production, renin inhibitors have been pursued as an additional class of anti-hypertensives. Clinical studies conducted with renin inhibitors have shown them to be as effective as ACE inhibitors in lowering blood pressure. Most importantly, inhibitors of renin may have a number of potential advantages over ACEi and ARBs. Renin is specific for angiotensinogen and will not carry the ancillary pharmacology associated with ACEi or ARBs. To date, no renin inhibitors have made it to market. The development of these inhibitors has been hindered by poor bioavailability and complex synthesis. However, despite the pharmacokinetic challenges of designing renin inhibitors, the enzyme remains a promising target for the development of novel treatments for hypertension. This review will consist of an overview of renin biology, the pharmacology of renin and RAS and focus in on renin as a target for blood pressure regulation. We also cover the evaluation of renin inhibitors in animal models and clinical studies. Presently a number of new generation inhibitors of renin are in development with at least one in the clinic and these will be discussed. Finally we will discuss what might distinguish renin inhibitors from current therapeutic options and discuss other therapeutic indications renin inhibitors might have.
Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Renina/antagonistas & inibidores , Sequência de Aminoácidos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Hipertensão/fisiopatologia , Modelos Animais , Modelos Biológicos , Dados de Sequência Molecular , Renina/genética , Renina/metabolismo , Sistema Renina-Angiotensina/fisiologiaRESUMO
Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.
RESUMO
Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11ß-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000× selectivity over 11ß-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adipócitos/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Oxazinas/química , Adipócitos/citologia , Adipócitos/enzimologia , Administração Oral , Animais , Células CHO , Células Cultivadas , Cortisona/farmacologia , Cricetinae , Cricetulus , Inibidores Enzimáticos/farmacocinética , Humanos , Macaca fascicularis , Camundongos , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
ABSTRACT Transient receptor potential (TRP) channels have been found to play important roles in cellular physiology and hold promise as therapeutic targets. These channels activate in response to a variety of chemical or physical stimuli and conduct non-selective cation currents (NSCC). Due to their unique activation properties, application of automated electrophysiology to measure the channel activity has been difficult. Using HEK293 cells stably expressing human TRP channels, hTRPC6 and hTRPA1, we developed and validated a high-throughput Rb(+) efflux assay for NSCC channels. The assay was performed in cell-based 96-well format. A significant increase in Rb(+) efflux can be detected upon channel activation by specific agonists, confirming that both TRPC6 and TRPA1 channels are permeable to Rb(+) ions. The agonists induced Rb(+) efflux can be blocked by known channel blockers and selected compounds from our high-throughput screening (HTS) hits. The assay is suitable for HTS with Z' factors of 0.53 and above. We also tested the Ca(2+) effect on channel activities in this assay. Both TRPC6 and TRPA1 channels were found to be inhibited by increasing the concentration of Ca(2+) in the assay buffer. However, Ca(2+) significantly reduced the potency of allyl isothiocyanate (AITC) on TRPA1 but did not affect the potency of carbochol on TRPC6. Using this assay for secondary confirmation screen, we successfully identified and confirmed the positive hits as TRPC6 inhibitors.
Assuntos
Canais Iônicos/efeitos dos fármacos , Canais Iônicos/metabolismo , Rubídio/metabolismo , Soluções Tampão , Canais de Cálcio/efeitos dos fármacos , Cátions/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Cinética , Proteínas do Tecido Nervoso/efeitos dos fármacos , Técnicas de Patch-Clamp , Canal de Cátion TRPA1 , Canais de Cátion TRPC/efeitos dos fármacos , Canal de Cátion TRPC6 , Canais de Potencial de Receptor Transitório/efeitos dos fármacosRESUMO
TRPA1 channels have been found to play an important role in mammalian pain sensation, especially when the pain is caused by chemicals on site of inflammation. A large number of structurally diverse chemicals are found to activate TRPA1 channels, implicating a potential chemosensor in neuronal nociception. Identification of the channel activation by cysteine modification through covalent chemical reaction provides arguments for the diversity of the agonist structures. However, it is largely unknown how nonreactive compounds activate TRPA1 channels. Here, we report that NPPB, a classic Cl(-) channel blocker, potently activated human TRPA1 channels overexpressed in mammalian HEK-293 cells. This effect was confirmed in Ca(2+) imaging assay, patch clamp whole cell and single channel recordings. The NPPB response was quick, fully reversible and replicable, contrary to the effect of covalent modification by AITC. The mutagenesis studies revealed a refreshed look at several mutations known to be critical for the actions of AITC and menthol. The blocking profile of NPPB on these mutants showed that the NPPB activation was similar to that of FTS and different from AITC and menthol. The results indicated a possible close interaction between S5 and N-terminal domains of the channel. We also tested a group of NPPB analogs on TRPA1 channel activities. The results demonstrated that NPPB activation was tightly associated with chemical structure. None of the single chemical group was sufficient to activate the channel, indicating that NPPB activated TRPA1 through a structure-specific mechanism.
Assuntos
Canais de Cálcio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nitrobenzoatos/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/fisiologia , Linhagem Celular , Humanos , Isotiocianatos/farmacologia , Rim/citologia , Mentol/farmacologia , Mutagênese , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nitrobenzoatos/química , Dor , Técnicas de Patch-Clamp/métodos , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/fisiologiaRESUMO
Voltage-gated K(+) channels are potential drug targets for an increasing number of disease indications. Searching for compounds that modulate K(+) channel activities by high-throughput screening (HTS) is becoming a standard approach in the drug discovery effort. Here the authors report an improved fluorometric imaging plate reader (FLIPR) membrane potential assay for Kv1.3 K(+) channel HTS. They have found that the Chinese hamster ovary (CHO) cells have endogenous membrane electrogenic transporters that contribute to maintaining membrane potential. Blocking the recombinant K(+) channels in the overexpressing CHO cell line hardly changed the membrane potential. Inhibition of the endogenous transporters is essential to achieve the required assay robustness. The authors identified the optimal assay conditions and designed a simple assay format. After an HTS campaign using this assay, various chemical series of Kv1.3 channel blockers have been identified and confirmed by the automated electrophysiological IonWorks assay. The correlation in dose response between FLIPR and IonWorks was established by biophysical modeling and experimental data. After characterization using patch-clamp recording, both use-dependent and use-independent compounds were identified. Some compounds possess nanomolar potency, indicating that the FLIPR assay is effective for successfully identifying K(+) channel blockers as novel drug candidates.
Assuntos
Bioensaio , Ensaios de Triagem em Larga Escala , Canal de Potássio Kv1.3/antagonistas & inibidores , Potenciais da Membrana/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eletrofisiologia , Fluorometria , Concentração Inibidora 50 , Técnicas de Patch-Clamp , Azida Sódica/farmacologiaRESUMO
Peroxisome proliferator-activated receptor alpha (PPARalpha) is the nuclear receptor responsible for regulating genes that control lipid homeostasis. Because of this role, PPARalpha has become a target of interest for the development of drugs to treat diseases such as dyslipidemia, obesity, and atherosclerosis. Assays currently employed to determine potency and efficacy of potential drug candidates typically utilize a truncated form of the native receptor, one which lacks the entire N-terminal region of the protein. The amino terminus, containing the regions that encode the ligand-independent activation function AF-1 and DNA binding domains, is highly structured and contributes significantly to the overall tertiary structure of the native protein. We report that differences in PPARalpha full-length and ligand binding domain constructs result in differences in binding affinity for coactivator peptides but have little effect on potency of agonists in both cell-free and cell-based nuclear receptor assays.
Assuntos
Proteínas de Ligação a DNA/agonistas , Proteínas de Ligação a DNA/química , PPAR alfa/agonistas , PPAR alfa/química , Sítios de Ligação , Sistema Livre de Células , Células Cultivadas , Humanos , Rim/metabolismo , Ligantes , Fragmentos de Peptídeos/química , Plasmídeos/metabolismo , Ativação TranscricionalRESUMO
CYP2D6 and CYP3A4 represent two particularly important members of the cytochrome p450 enzyme family due to their involvement in the metabolism of many commercially available drugs. Avoiding potent inhibitory interactions with both of these enzymes is highly desirable in early drug discovery, long before entering clinical trials. Computational prediction of this liability as early as possible is desired. Using a commercially available data set of over 1750 molecules to train computer models that were generated with commercially available software enabled predictions of inhibition for CYP2D6 and CYP3A4, which were compared with empirical data. The results suggest that using a recursive partitioning (tree) technique with augmented atom descriptors enables a statistically significant rank ordering of test-set molecules (Spearman's rho of 0.61 and 0.48 for CYP2D6 and CYP3A4, respectively), which represents an increased rate of identifying the best compounds when compared with the random rate. This approach represents a valuable computational filter in early drug discovery to identify compounds that may have p450 inhibition liabilities prior to molecule synthesis. Such computational filters offer a new approach in which lead optimization in silico can occur with virtual molecules simultaneously tested against multiple enzymes implicated in drug-drug interactions, with a resultant cost savings from a decreased level of molecule synthesis and in vitro screening.
Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Citocromo P-450 CYP2D6/química , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/química , Modelos Biológicos , Biologia Computacional , Cumarínicos/química , Citocromo P-450 CYP3A , Bases de Dados Factuais , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Relação Quantitativa Estrutura-Atividade , Compostos de Amônio Quaternário/química , Reprodutibilidade dos Testes , SoftwareRESUMO
PURPOSE: We aimed to investigate the degree of participation of synovial sheath cells in the process of tendon healing by selective cell labeling and direct observation of migrational pathways. METHODS: We designed a novel rat animal model that employed vital dye staining of synovial sheath cells. The flexor digitorum profundus (FDP) tendon was removed from its sheath and vital dye was applied directly to the synovial sheath cells. A window was cut in the removed tendon before being returned to the sheath, thus placing a tendon injury adjacent to the labeled synovial sheath cells. The synovium remained intact at all times, and labeling was confirmed to be localized to the synovium. The migrational response of the synovial sheath cells to the tendon injury was observed by harvesting the tendons at 1, 3, 5, and 7 days (n = 6 for each time period) after injury and assessing tendon response with frozen sections under ultraviolet microscopy. RESULTS: Labeled synovial sheath cells were observed within the substance of the healing tendon 24 hours after injury, with numbers increasing with time for up to 5 days, but decreasing by day 7. CONCLUSIONS: This study confirms that in the rat model synovial sheath cells move into the healing tendon area and then migrate into the tendon core.
Assuntos
Movimento Celular , Membrana Sinovial/citologia , Traumatismos dos Tendões/fisiopatologia , Cicatrização/fisiologia , Animais , Contagem de Células , Secções Congeladas , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
A cDNA encoding human prepro-cathepsin E was introduced into the adenovirus-transformed HEK-293 (human embryonic kidney) cell line. The construct contained both a V5 peptide epitope and histidine tags at the carboxy terminus. Transfected cells efficiently secreted recombinant pro-cathepsin E into the culture medium. The secreted pro-cathepsin E was purified in a single step using Ni affinity chromatography yielding a protein of about 92 kDa under non-reducing conditions. The amino-terminal sequence of the purified protein began at Ser20, suggesting human cathepsin E accumulated in the culture supernatant as the pro-enzyme. The purified protein was rapidly and completely converted to the active form by treatment at pH 4.0 or below. Steady state kinetic parameters for hydrolysis of the fluorogenic peptide substrate MOCAc-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-d-Arg-NH2 (cleavage at the Phe-Phe bond) were consistent with previously reported values for purified human enzyme (kc/Ki= 53 x 10(6) M(-1) s(-1), Km= 6.3 microM, and kcat= 3 x 10(2) s(-1)). The activated protein was potently inhibited by pepstatin with Ki= 0.2 nM, as well as a reported beta secretase inhibitor. This work demonstrates the potential for producing large quantities of highly purified human cathepsin E from HEK-293 cells in quantities to support both biochemical and structural characterization of the enzyme.
Assuntos
Catepsina E/isolamento & purificação , Catepsina E/metabolismo , Catepsinas/isolamento & purificação , Catepsinas/metabolismo , Precursores Enzimáticos/isolamento & purificação , Precursores Enzimáticos/metabolismo , Rim/citologia , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Sequência de Aminoácidos , Catepsina E/química , Catepsina E/genética , Catepsinas/química , Catepsinas/genética , Linhagem Celular , Clonagem Molecular , Ativação Enzimática , Precursores Enzimáticos/química , Precursores Enzimáticos/genética , Humanos , Concentração de Íons de Hidrogênio , Dados de Sequência Molecular , Estrutura Molecular , Peso Molecular , Proteínas Recombinantes/química , Proteínas Recombinantes/genéticaRESUMO
The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors activated by fatty acids and their metabolites. The PPARdelta subtype is believed to be involved in lipoprotein regulation and may have a role in reverse cholesterol transport. While the range of biological roles of PPARdelta still remains unclear, it is of therapeutic interest in cardiovascular diseases. Here we report a homogeneous in vitro assay for studying ligand activation of PPARdelta. We surveyed a panel of peptides containing the LXXLL motifs derived from coactivator protein sequences. Peptides with the best response were used to develop a sensitive and homogeneous recruitment assay for PPARdelta. The optimized assay has a signal-to-background ratio of about 8:1 and an assay quality parameter Z'-factor value of 0.8. The assay signal generated is stable for hours to even overnight. This simple recruitment assay can provide agonist and/or antagonist information that cannot be assessed by receptor-binding assay, and can be used for characterization and screening of ligands that modulate the activation of PPARdelta.