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1.
J Med Chem ; 67(13): 10567-10588, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38917049

RESUMO

G protein-coupled receptor G2A was postulated to be a promising target for the development of new therapeutics in neuropathic pain, acute myeloid leukemia, and inflammation. However, there is still a lack of potent, selective, and drug-like G2A agonists to be used as a chemical tool or as the starting matter for the development of drugs. In this work, we present the discovery and structure-activity relationship elucidation of a new potent and selective G2A agonist scaffold. Systematic optimization resulted in (3-(pyridin-3-ylmethoxy)benzoyl)-d-phenylalanine (T-10418) exhibiting higher potency than the reference and natural ligand 9-HODE and high selectivity among G protein-coupled receptors. With its favorable activity, a clean selectivity profile, excellent solubility, and high metabolic stability, T-10418 qualifies as a pharmacological tool to investigate the effects of G2A activation.


Assuntos
Receptores Acoplados a Proteínas G , Humanos , Relação Estrutura-Atividade , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Animais , Fenilalanina/farmacologia , Fenilalanina/análogos & derivados , Fenilalanina/química , Fenilalanina/síntese química , Estrutura Molecular
2.
J Med Chem ; 67(5): 3813-3842, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38422480

RESUMO

Mammalian STE20-like (MST) kinases 1-4 play key roles in regulating the Hippo and autophagy pathways, and their dysregulation has been implicated in cancer development. In contrast to the well-studied MST1/2, the roles of MST3/4 are less clear, in part due to the lack of potent and selective inhibitors. Here, we re-evaluated literature compounds, and used structure-guided design to optimize the p21-activated kinase (PAK) inhibitor G-5555 (8) to selectively target MST3/4. These efforts resulted in the development of MR24 (24) and MR30 (27) with good kinome-wide selectivity and high cellular potency. The distinct cellular functions of closely related MST kinases can now be elucidated with subfamily-selective chemical tool compounds using a combination of the MST1/2 inhibitor PF-06447475 (2) and the two MST3/4 inhibitors developed. We found that MST3/4-selective inhibition caused a cell-cycle arrest in the G1 phase, whereas MST1/2 inhibition resulted in accumulation of cells in the G2/M phase.


Assuntos
Proteínas Serina-Treonina Quinases , Quinases Ativadas por p21 , Animais , Proteínas Serina-Treonina Quinases/metabolismo , Mamíferos/metabolismo
4.
J Med Chem ; 67(1): 674-690, 2024 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-38126712

RESUMO

MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20-like serine/threonine (MST) family that regulate cellular functions such as proliferation and migration. The MST3 isozyme plays a role in regulating cell growth and apoptosis, and its dysregulation has been linked to high-grade tumors. To date, there are no isoform-selective inhibitors that could be used for validating the role of MST3 in tumorigenesis. We designed a series of 3-aminopyrazole-based macrocycles based on the structure of a promiscuous inhibitor. By varying the moieties targeting the solvent-exposed region and optimizing the linker, macrocycle JA310 (21c) was synthesized. JA310 exhibited high cellular potency for MST3 (EC50 = 106 nM) and excellent kinome-wide selectivity. The crystal structure of the MST3-JA310 complex provided intriguing insights into the binding mode, which is associated with large-scale structural rearrangements. In summary, JA310 demonstrates the utility of macrocyclization for the design of highly selective inhibitors and presents the first chemical probe for MST3.


Assuntos
Apoptose , Proteínas Serina-Treonina Quinases , Animais , Proteínas Serina-Treonina Quinases/metabolismo , Fosforilação , Mamíferos/metabolismo
5.
Lancet Reg Health Eur ; 37: 100810, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38076629

RESUMO

Background: SARS-CoV-2 infections still have a significant impact on the global population. The existing vaccinations have contributed to reducing the severe disease courses, decreasing hospitalisations, and lowering the mortality rate. However, due to the variability of COVID-19 symptoms, the emergence of new variants and the uneven global distribution of vaccines there is still a great need for new therapy options. One promising approach is provided by host-directed therapies. We assessed here the efficacy and safety of MP1032, a host-directed anti-viral/anti-inflammatory drug in hospitalised patients with moderate to severe COVID-19. Methods: In a randomised, double-blind, placebo-controlled, Phase IIa study, patients were randomised 2:1 to receive either 300 mg MP032 bid + Standard-of-Care (SoC) or placebo bid + SoC for 28 days. Eligible patients were ≥18 years old, tested positive for SARS-CoV-2, and had moderate to severe COVID-19 symptoms. The study spanned 20 sites in six countries (Bulgaria, France, Hungary, Italy, Romania, Spain), assessing disease progression according the NIAID scale as the primary outcome on day 14. Secondary objectives included disease progression (day 28), disease resolution (days 14 and 28), mortality rate, COVID-19 related parameters and safety. Exposure-response analyses were performed, linking MP1032 to COVID-19 biomarkers (eGFR, D-dimer). Findings: 132 patients were enrolled to receive MP1032 + SoC (n = 87) or placebo + SoC (n = 45). The patients were all white or Caucasian with a mean (median) age of 60.5 (63) years. Overall, only 10 patients were vaccinated, 5 in each group. No significant risk difference of disease progression could be detected between groups on both day 14 (9.8% MP1032 vs. 11.6% placebo) and day 28 with MH common risk differences of -0.276% (95% CI, -11.634 to 11.081; p = 0.962) and 1.722% (95% CI, -4.576 to 8.019; p = 0.592), respectively.The treatment with MP1032 + SoC was safe and well-tolerated. Overall, 182 TEAEs including 10 SAEs were reported in 53.5% (46/86) of patients of the verum group and in 57.8% (26/45) of patients of the placebo group; the SAEs occurred in 5.8% (5/86) and 6.7% (3/45) of verum and placebo patients, respectively. None of the SAEs was considered as related. Interpretation: Despite the study's limitation in size and the variation in concurrent SoCs, these findings warrant further investigation of MP1032 as a host-directed anti-viral drug candidate. Funding: The study was funded by the COVID-19 Horizon Europe work programme and MetrioPharm AG.

6.
J Am Chem Soc ; 145(27): 14802-14810, 2023 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-37385602

RESUMO

The lipid-sensing transcription factor PPARγ is the target of antidiabetic thiazolidinediones (TZD). At two sites within its ligand binding domain, it also binds oxidized vitamin E metabolites and the vitamin E mimetic garcinoic acid. While the canonical interaction within the TZD binding site mediates classical PPARγ activation, the effects of the second binding on PPARγ activity remain elusive. Here, we identified an agonist mimicking dual binding of vitamin E metabolites and developed a selective ligand of the second site, unveiling potential noncanonical regulation of PPARγ activities. We found that this alternative binding event can simultaneously occur with orthosteric ligands and it exerted different effects on PPARγ-cofactor interactions compared to both orthosteric PPARγ agonists and antagonists, indicating the diverse roles of the two binding sites. Alternative site binding lacked the pro-adipogenic effect of TZD and mediated no classical PPAR signaling in differential gene expression analysis but markedly diminished FOXO signaling, suggesting potential therapeutic applications.


Assuntos
PPAR gama , Tiazolidinedionas , PPAR gama/agonistas , PPAR gama/genética , PPAR gama/metabolismo , Ligantes , Fatores de Transcrição/metabolismo , Tiazolidinedionas/química , Sítios de Ligação
7.
Int J Mol Sci ; 23(23)2022 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-36499165

RESUMO

The PCTAIRE subfamily belongs to the CDK (cyclin-dependent kinase) family and represents an understudied class of kinases of the dark kinome. They exhibit a highly conserved binding pocket and are activated by cyclin Y binding. CDK16 is targeted to the plasma membrane after binding to N-myristoylated cyclin Y and is highly expressed in post-mitotic tissues, such as the brain and testis. Dysregulation is associated with several diseases, including breast, prostate, and cervical cancer. Here, we used the N-(1H-pyrazol-3-yl)pyrimidin-4-amine moiety from the promiscuous inhibitor 1 to target CDK16, by varying different residues. Further optimization steps led to 43d, which exhibited high cellular potency for CDK16 (EC50 = 33 nM) and the other members of the PCTAIRE and PFTAIRE family with 20-120 nM and 50-180 nM, respectively. A DSF screen against a representative panel of approximately 100 kinases exhibited a selective inhibition over the other kinases. In a viability assessment, 43d decreased the cell count in a dose-dependent manner. A FUCCI cell cycle assay revealed a G2/M phase cell cycle arrest at all tested concentrations for 43d, caused by inhibition of CDK16.


Assuntos
Quinases Ciclina-Dependentes , Ciclinas , Masculino , Humanos , Ciclinas/metabolismo , Sequência de Aminoácidos , Quinases Ciclina-Dependentes/metabolismo , Ligação Proteica
8.
J Med Chem ; 64(23): 17259-17276, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34818007

RESUMO

Polypharmaceutical regimens often impair treatment of patients with metabolic syndrome (MetS), a complex disease cluster, including obesity, hypertension, heart disease, and type II diabetes. Simultaneous targeting of soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptor γ (PPARγ) synergistically counteracted MetS in various in vivo models, and dual sEH inhibitors/PPARγ agonists hold great potential to reduce the problems associated with polypharmacy in the context of MetS. However, full activation of PPARγ leads to fluid retention associated with edema and weight gain, while partial PPARγ agonists do not have these drawbacks. In this study, we designed a dual partial PPARγ agonist/sEH inhibitor using a structure-guided approach. Exhaustive structure-activity relationship studies lead to the successful optimization of the designed lead. Crystal structures of one representative compound with both targets revealed potential points for optimization. The optimized compounds exhibited favorable metabolic stability, toxicity, selectivity, and desirable activity in adipocytes and macrophages.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , PPAR gama/agonistas , Animais , Cristalografia por Raios X , Células HEK293 , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Polimedicação , Ratos , Relação Estrutura-Atividade
9.
J Med Chem ; 64(13): 9525-9536, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34165993

RESUMO

Non-alcoholic steatohepatitis (NASH) presents as an epidemic chronic liver disease that is closely associated with metabolic disorders and involves hepatic steatosis, inflammation, and fibrosis as key factors. Despite the enormous global prevalence of NASH, effective pharmacological interventions are lacking. Based on the hypothesis that the multifactorial condition NASH may benefit from combined multiple modes of action for enhanced therapeutic efficacy, we have previously developed dual FXR activators/sEH inhibitors (FXRa/sEHi) and observed remarkable antifibrotic effects upon their use in rodent NASH models. However, these first-generation FXRa/sEHi were characterized by moderate metabolic stability and short in vivo half-life. Aiming to overcome these pharmacokinetic drawbacks, we have systematically studied the structure-activity and structure-stability relationships of the chemotype and obtained second-generation FXRa/sEHi with improved pharmacokinetic parameters. With high plasma exposure, a half-life greater than 5 h, and similar dual potency on the intended targets, 13 presents as a substantially optimized FXRa/sEHi for late-stage preclinical development.


Assuntos
Benzamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Benzamidas/síntese química , Benzamidas/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Epóxido Hidrolases/metabolismo , Células Hep G2 , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Relação Estrutura-Atividade
10.
J Med Chem ; 64(12): 8727-8738, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34115934

RESUMO

The ligand-sensing transcription factor tailless homologue (TLX, NR2E1) is an essential regulator of neuronal stem cell homeostasis with appealing therapeutic potential in neurodegenerative diseases and central nervous system tumors. However, knowledge on TLX ligands is scarce, providing an obstacle to target validation and medicinal chemistry. To discover TLX ligands, we have profiled a drug fragment collection for TLX modulation and identified several structurally diverse agonists and inverse agonists of the nuclear receptor. Propranolol evolved as the strongest TLX agonist and promoted TLX-regulated gene expression in human glioblastoma cells. Structure-activity relationship elucidation of propranolol as a TLX ligand yielded a structurally related negative control compound. In functional cellular experiments, we observed an ability of propranolol to counteract glioblastoma cell proliferation and migration, while the negative control had no effect. Our results provide a collection of TLX modulators as initial chemical tools and set of lead compounds and support therapeutic potential of TLX modulation in glioblastoma.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Propranolol/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Linhagem Celular Tumoral , Células HEK293 , Humanos , Estrutura Molecular , Receptores Nucleares Órfãos , Relação Estrutura-Atividade
11.
ACS Pharmacol Transl Sci ; 4(2): 966-979, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33860214

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is an epidemic chronic liver disease and may progress over nonalcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma. The multiple metabolic, environmental, and genetic factors that are involved in NAFLD/NASH pathogenesis and progression suggest a need for multimechanistic interventions. We have developed and preliminarily characterized a concept of dual farnesoid X receptor (FXR) and soluble epoxide hydrolase (sEH) modulation as a promising polypharmacological strategy to counteract NASH. Here we report the profiling of FXR activation, sEH inhibition, and simultaneous FXR/sEH modulation as an interventional treatment in pre-established NASH in mice with diet-induced obesity (DIO). We found that full FXR activation was required to obtain antisteatosis effects but also worsened ballooning degeneration and fibrosis. In contrast, sEH inhibition and dual FXR/sEH modulation, despite a lack of antisteatosis activity, had anti-inflammatory effects and efficiently counteracted hepatic fibrosis. These results demonstrate great therapeutic potential of sEH inhibition to counteract hepatic fibrosis and validate the designed polypharmacology concept of dual FXR/sEH modulation as a potentially superior avenue for the effective treatment of the multifactorial condition NASH.

12.
ACS Med Chem Lett ; 12(2): 267-274, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33603974

RESUMO

Therapeutic modulation of the bile acid-sensing transcription factor farnesoid X receptor (FXR) is an appealing strategy to counteract hepatic and metabolic diseases. Despite the availability of several highly potent FXR agonists structural diversity of FXR modulators is limited, and new ligand scaffolds are needed. Here we report structure-activity relationship elucidation of a new FXR modulator chemotype whose activity can be tuned between agonism and antagonism by two minor structural modifications. Starting from a weak FXR/PPAR agonist, we have developed selective FXR activators and antagonists with nanomolar to low-micromolar potencies and binding affinities. The new FXR ligand chemotype modulates the FXR activity in the native cellular setting, is endowed with favorable metabolic stability, and lacks cytotoxicity. It valuably expands the collection of FXR modulators as a new scaffold for FXR-targeted drug discovery.

13.
Int J Mol Sci ; 21(22)2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33233817

RESUMO

At least since March 2020, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic and the multi-organ coronavirus disease 2019 (COVID-19) are keeping a firm grip on the world. Although most cases are mild, older patients and those with co-morbidities are at increased risk of developing a cytokine storm, characterized by a systemic inflammatory response leading to acute respiratory distress syndrome and organ failure. The present paper focuses on the small molecule MP1032, describes its mode of action, and gives rationale why it is a promising option for the prevention/treatment of the SARS-CoV-2-induced cytokine storm. MP1032 is a phase-pure anhydrous polymorph of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt that exhibits good stability and bioavailability. The physiological action of MP1032 is based on a multi-target mechanism including localized, self-limiting reactive oxygen species (ROS) scavenging activities that were demonstrated in a model of lipopolysaccharide (LPS)-induced joint inflammation. Furthermore, its immune-regulatory and PARP-1-modulating properties, coupled with antiviral effects against SARS-CoV-2, have been demonstrated in various cell models. Preclinical efficacy was elucidated in LPS-induced endotoxemia, a model with heightened innate immune responses that shares many similarities to COVID-19. So far, during oral clinical development with three-month daily administrations, no serious adverse drug reactions occurred, highlighting the outstanding safety profile of MP1032.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Luminol/análogos & derivados , Pneumonia Viral/tratamento farmacológico , Aminação , Animais , Antivirais/química , Betacoronavirus/imunologia , COVID-19 , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Feminino , Humanos , Fatores Imunológicos/química , Inflamação/imunologia , Luminol/química , Luminol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Pneumonia Viral/imunologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/imunologia , Espécies Reativas de Oxigênio/imunologia , SARS-CoV-2 , Células Vero
14.
J Med Chem ; 63(20): 11498-11521, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33044073

RESUMO

Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation- and fibrosis-related disease models.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Araquidonato 5-Lipoxigenase/metabolismo , Desenho de Fármacos , Epóxido Hidrolases/antagonistas & inibidores , Inibidores de Lipoxigenase/síntese química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Araquidonato 5-Lipoxigenase/genética , Células Cultivadas , Epóxido Hidrolases/genética , Humanos , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Ligação Proteica , Ratos , Relação Estrutura-Atividade
15.
J Med Chem ; 63(20): 11548-11572, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32946232

RESUMO

The first potent leukotriene B4 (LTB4) receptor type 2 (BLT2) agonists, endogenous 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT), and synthetic CAY10583 (CAY) have been recently described to accelerate wound healing by enhanced keratinocyte migration and indirect stimulation of fibroblast activity in diabetic rats. CAY represents a very valuable starting point for the development of novel wound-healing promoters. In this work, the first structure-activity relationship study for CAY scaffold-based BLT2 agonists is presented. The newly prepared derivatives showed promising in vitro wound-healing activity.


Assuntos
Desenvolvimento de Medicamentos/métodos , Queratinócitos/efeitos dos fármacos , Receptores do Leucotrieno B4/agonistas , Cicatrização/efeitos dos fármacos , Animais , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Células HaCaT , Células Hep G2 , Humanos , Queratinócitos/metabolismo , Estrutura Molecular , Receptores do Leucotrieno B4/genética , Relação Estrutura-Atividade , Cicatrização/fisiologia
16.
J Med Chem ; 63(15): 8369-8379, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32687365

RESUMO

Nonalcoholic steatohepatitis (NASH) is considered as severe hepatic manifestation of the metabolic syndrome and has alarming global prevalence. The ligand-activated transcription factors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) δ have been validated as molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPARδ-mediated activity and hepatic effects of FXR activation appear as a promising multitarget approach. We have designed a minimal dual FXR/PPARδ activator scaffold by rational fusion of pharmacophores derived from selective agonists. Our dual agonist lead compound exhibited weak agonism on FXR and PPARδ and was structurally refined to a potent and balanced FXR/PPARδ activator in a computer-aided fashion. The resulting dual FXR/PPARδ modulator comprises high selectivity over related nuclear receptors and activates the two target transcription factors in native cellular settings.


Assuntos
PPAR delta/agonistas , Receptores Citoplasmáticos e Nucleares/agonistas , Desenho de Fármacos , Descoberta de Drogas , Humanos , Ligantes , Simulação de Acoplamento Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR delta/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade
17.
Commun Chem ; 3(1): 174, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-36703463

RESUMO

Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.

18.
ChemMedChem ; 15(1): 50-67, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31670489

RESUMO

The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non-alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti-NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti-asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver-related metabolic diseases.


Assuntos
Epóxido Hidrolases/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/agonistas , Compostos de Tosil/química , Sítios de Ligação , Domínio Catalítico , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Avaliação Pré-Clínica de Medicamentos , Epóxido Hidrolases/genética , Epóxido Hidrolases/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Indóis , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Simulação de Acoplamento Molecular , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Fenilcarbamatos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade , Sulfonamidas , Compostos de Tosil/metabolismo , Compostos de Tosil/farmacologia
19.
ACS Med Chem Lett ; 10(9): 1346-1352, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31531208

RESUMO

The nuclear retinoid X receptors (RXRs) are key ligand sensing transcription factors that serve as universal nuclear receptor heterodimer partners and are thus involved in numerous physiological processes. Therapeutic targeting of RXRs holds high potential but available RXR activators suffer from limited safety. Selectivity for RXR subtypes or for certain RXR heterodimers are promising strategies for safer RXR modulation. Here, we report systematic structure-activity relationship studies on biphenyl carboxylates as new RXR ligand chemotype. We discovered specific structural modifications that enhance potency on RXRs, govern subtype preference, and vary modulation of different RXR heterodimers. Fusion of these structural motifs enabled specific tuning of subtype preferential profiles with markedly improved potency. Our results provide further evidence that RXR subtype selective ligands can be designed and present a novel chemotype of RXR modulators that can be tuned for subtype and heterodimer preferences.

20.
Bioorg Med Chem ; 27(21): 115082, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31548084

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARγ) modulators have found wide application for the treatment of cancers, metabolic disorders and inflammatory diseases. Contrary to PPARγ agonists, PPARγ antagonists have been much less studied and although they have shown immunomodulatory effects, there is still no therapeutically useful PPARγ antagonist on the market. In contrast to non-competitive, irreversible inhibition caused by 2-chloro-5-nitrobenzanilide (GW9662), the recently described (E)-2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4-(trifluoromethyl)benzyl)oxy)-benzylidene)-hexanoic acid (MTTB, T-10017) is a promising prototype for a new class of PPARγ antagonists. It exhibits competitive antagonism against rosiglitazone mediated activation of PPARγ ligand binding domain (PPARγLBD) in a transactivation assay in HEK293T cells with an IC50 of 4.3 µM against 1 µM rosiglitazone. The aim of this study was to investigate the structure-activity relationships (SAR) of the MTTB scaffold focusing on improving its physicochemical properties. Through this optimization, 34 new derivatives were prepared and characterized. Two new potent compounds (T-10075 and T-10106) with much improved drug-like properties and promising pharmacokinetic profile were identified.


Assuntos
Cinamatos/farmacologia , PPAR gama/antagonistas & inibidores , Quinolinas/farmacologia , Animais , Cinamatos/síntese química , Cinamatos/farmacocinética , Células HEK293 , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Rosiglitazona/farmacologia , Relação Estrutura-Atividade
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