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1.
Nat Commun ; 10(1): 2915, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266946

RESUMO

The bile acid-sensing transcription factor farnesoid X receptor (FXR) regulates multiple metabolic processes. Modulation of FXR is desired to overcome several metabolic pathologies but pharmacological administration of full FXR agonists has been plagued by mechanism-based side effects. We have developed a modulator that partially activates FXR in vitro and in mice. Here we report the elucidation of the molecular mechanism that drives partial FXR activation by crystallography- and NMR-based structural biology. Natural and synthetic FXR agonists stabilize formation of an extended helix α11 and the α11-α12 loop upon binding. This strengthens a network of hydrogen bonds, repositions helix α12 and enables co-activator recruitment. Partial agonism in contrast is conferred by a kink in helix α11 that destabilizes the α11-α12 loop, a critical determinant for helix α12 orientation. Thereby, the synthetic partial agonist induces conformational states, capable of recruiting both co-repressors and co-activators leading to an equilibrium of co-activator and co-repressor binding.


Assuntos
Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/química , Animais , Linhagem Celular , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Humanos , Ligações de Hidrogênio , Ligantes , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Conformação Proteica em alfa-Hélice , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo
2.
J Med Chem ; 60(16): 7199-7205, 2017 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-28749691

RESUMO

As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.


Assuntos
Imidazóis/farmacologia , Piridinas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Colesterol 7-alfa-Hidroxilase/genética , Estabilidade de Medicamentos , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/metabolismo , Masculino , Proteínas de Membrana Transportadoras/genética , Simulação de Acoplamento Molecular , PPAR alfa/genética , Piridinas/síntese química , Piridinas/química , Piridinas/metabolismo , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Relação Estrutura-Atividade , Zolpidem
3.
Future Med Chem ; 8(2): 133-48, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26824277

RESUMO

BACKGROUND: Bile acids can serve as signaling molecules by activating the nuclear receptor FXR and the G-protein-coupled receptor TGR5 and both bile acid receptors are prominent experimental drug targets. Results/methodology: In this study we optimized the fatty acid mimetic compound pirinixic acid to a new scaffold with the aim to develop novel FXR modulatory compounds. After a multistep structure-activity optimization process, we discovered FXR agonistic compounds and the first dual FXR antagonistic and TGR5 agonistic compound 79a. CONCLUSION: With this novel dual activity profile on both bile acid receptors 79a might be a valuable pharmalogical tool to further study the bile acid signaling network.


Assuntos
Ácidos e Sais Biliares/química , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/agonistas , Ácido Benzoico/química , Ácido Benzoico/farmacologia , Ácidos e Sais Biliares/farmacologia , Linhagem Celular Tumoral , Células HeLa , Humanos , Ligação Proteica , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacos
4.
J Med Chem ; 59(1): 61-81, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26595749

RESUMO

Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, and obesity. MetS patients are strongly exposed to polypharmacy; however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multitarget compounds. This study describes the design of dual-target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type γ (PPARγ). Simultaneous modulation of sEH and PPARγ can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPARγ pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 µM/PPARγ EC50 = 0.3 µM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long-term animal models of MetS.


Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Síndrome Metabólica/tratamento farmacológico , PPAR gama/efeitos dos fármacos , Células 3T3 , Administração Oral , Animais , Benzamidas/farmacocinética , Células COS , Cercopithecus aethiops , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacocinética , Humanos , Hipertensão/tratamento farmacológico , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 25(4): 841-6, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25575659

RESUMO

We present the design, synthesis and biological evaluation of compounds containing a 2-(benzylidene)hexanoic acid scaffold as multi-target directed γ-secretase-modulators. Broad structural variations were undertaken to elucidate the structure-activity-relationships at the 5-position of the aromatic core. Compound 13 showed the most potent activity profile with IC50 values of 0.79µM (Aß42), 0.3µM (5-lipoxygenase) and an EC50 value of 4.64µM for PPARγ-activation. This derivative is the first compound exhibiting low micromolar to nanomolar activities for these three targets. Combining γ-secretase-modulation, PPARγ-agonism and inhibition of 5-lipoxygenase in one compound could be a novel disease-modifying multi-target-strategy for Alzheimer's disease to concurrently address the causative amyloid pathology and secondary pathologies like chronic brain inflammation.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Araquidonato 5-Lipoxigenase/efeitos dos fármacos , Caproatos/uso terapêutico , Inibidores de Lipoxigenase/farmacologia , PPAR gama/agonistas , Caproatos/química , Caproatos/farmacologia , Humanos , Inibidores de Lipoxigenase/uso terapêutico , Relação Estrutura-Atividade
6.
Bioorg Med Chem ; 23(3): 499-514, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25583100

RESUMO

Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of anthranilic acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism.


Assuntos
Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Citoplasmáticos e Nucleares/agonistas , ortoaminobenzoatos/farmacologia , Animais , Células COS , Cercopithecus aethiops , Ligantes , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/química , Receptores Citoplasmáticos e Nucleares/química , Relação Estrutura-Atividade , ortoaminobenzoatos/química
7.
Curr Top Med Chem ; 14(19): 2188-205, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25388533

RESUMO

The nuclear bile acid sensor farnesoid X receptor (FXR) constitutes a rising target for the treatment of a variety of diseases including metabolic disorders, inflammation and certain forms of cancer. While the research on FXR agonists has yielded many compounds and first clinical candidates, only few FXR antagonists have been discovered so far and the knowledge about their in vivo effects is quite narrow. We have evaluated available in vitro and in vivo studies with FXR antagonists as well as FXR knockout models to elucidate a potential pharmacological use of FXR antagonism. To date, the in vitro and in vivo data suggests that FXR inhibition by knockout or the use of antagonists causes beneficial effects on cholesterol metabolism, ameliorates liver toxicity in cholestasis and can reduce the proliferation and migration of some cancer cell lines. Unfortunately, also many disadvantageous effects are connected with FXR antagonists.


Assuntos
Química Farmacêutica , Doenças Metabólicas/tratamento farmacológico , Preparações Farmacêuticas/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Animais , Humanos , Modelos Moleculares
8.
Nat Chem ; 6(12): 1072-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25411885

RESUMO

Natural products have long been a source of useful biological activity for the development of new drugs. Their macromolecular targets are, however, largely unknown, which hampers rational drug design and optimization. Here we present the development and experimental validation of a computational method for the discovery of such targets. The technique does not require three-dimensional target models and may be applied to structurally complex natural products. The algorithm dissects the natural products into fragments and infers potential pharmacological targets by comparing the fragments to synthetic reference drugs with known targets. We demonstrate that this approach results in confident predictions. In a prospective validation, we show that fragments of the potent antitumour agent archazolid A, a macrolide from the myxobacterium Archangium gephyra, contain relevant information regarding its polypharmacology. Biochemical and biophysical evaluation confirmed the predictions. The results obtained corroborate the practical applicability of the computational approach to natural product 'de-orphaning'.


Assuntos
Produtos Biológicos/química , Descoberta de Drogas/métodos , Substâncias Macromoleculares/química , Ácido Araquidônico/química , Desenho de Drogas , Macrolídeos/química , Estrutura Molecular , Receptores Citoplasmáticos e Nucleares/fisiologia , Tiazóis/química , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores
9.
J Med Chem ; 57(19): 8035-55, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25255039

RESUMO

The ligand activated transcription factor nuclear farnesoid X receptor (FXR) is involved as a regulator in many metabolic pathways including bile acid and glucose homeostasis. Therefore, pharmacological activation of FXR seems a valuable therapeutic approach for several conditions including metabolic diseases linked to insulin resistance, liver disorders such as primary biliary cirrhosis or nonalcoholic steatohepatitis, and certain forms of cancer. The available FXR agonists, however, activate the receptor to the full extent which might be disadvantageous over a longer time period. Hence, partial FXR activators are required for long-term treatment of metabolic disorders. We here report the SAR of anthranilic acid derivatives as FXR modulators and development, synthesis, and characterization of compound 51, which is a highly potent partial FXR agonist in a reporter gene assay with an EC50 value of 8 ± 3 nM and on mRNA level in liver cells.


Assuntos
Receptores Citoplasmáticos e Nucleares/agonistas , ortoaminobenzoatos/síntese química , Animais , Descoberta de Drogas , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/química , Relação Estrutura-Atividade , ortoaminobenzoatos/farmacologia
10.
Bioorg Med Chem Lett ; 24(16): 3757-63, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25037914

RESUMO

The concept of dual PPARα/γ activation was originally proposed as a new approach for the treatment of the metabolic syndrome. However, recent results indicated that PPARα as well as PPARγ activation might also be beneficial in the treatment of inflammatory diseases and cancer. We have recently identified aminothiazole-featured pirinixic acids as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors. Here we present the structure-activity relationship of these aminothiazole-featured pirinixic acids as dual PPARα/γ agonists and discuss their advantages with their potential as dual 5-LO/mPGES-1 inhibitors in inflammatory and cancer diseases. Various pirinixic acid derivatives had already been identified as dual PPARα/γ agonists. However, within this series of aminothiazole-featured pirinixic acids we were able to identify the most potent selective PPARγ agonistic pirinixic acid derivative (compound 13, (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid)). Therefore, docking of 13 on PPARγ was performed to determine the potential binding mode.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Inibidores Enzimáticos/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , PPAR alfa/antagonistas & inibidores , PPAR gama/antagonistas & inibidores , Pirimidinas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Oxirredutases Intramoleculares/metabolismo , Modelos Moleculares , Estrutura Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Prostaglandina-E Sintases , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Tiazóis/química
11.
Bioorg Med Chem Lett ; 24(16): 4048-52, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25022880

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of the metabolic syndrome. Especially a combination of PPARα and PPARγ agonistic activity seems worthwhile to be pursued. Herein we present the design and synthesis of a series of pirinixic acid derivatives as potent PPARα particularly dual PPARα/γ agonists with 2-((4-chloro-6-((4-(phenylamino)phenyl)amino)pyrimidin-2-yl)thio)octanoicacid having the highest potential. Our investigations based on molecular docking and structure-activity relationship (SAR) studies elucidated structural determinants affecting the potency at PPARα. A diphenylamine-scaffold seems to play a key role. Careful in silico analysis revealed an essential role for a hydrogen bond between the diphenylamine and a water cluster. We confirmed this hypothesis using a mutated PPARα LBD in our transactivation assay to disrupt the water cluster and to validate the proposed interaction.


Assuntos
Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , PPAR alfa/agonistas , Pirimidinas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligações de Hidrogênio , Estrutura Molecular , PPAR alfa/genética , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
12.
Bioorg Med Chem ; 22(8): 2447-60, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24685112

RESUMO

Nuclear farnesoid X receptor (FXR) has important physiological roles in various metabolic pathways including bile acid, cholesterol and glucose homeostasis. The clinical use of known synthetic non-steroidal FXR ligands is restricted due to toxicity or poor bioavailability. Here we report the development, synthesis, in vitro activity and structure-activity relationship (SAR) of anthranilic acid derivatives as novel FXR ligands. Starting from a virtual screening hit we optimized the scaffold to a series of potent partial FXR agonists with appealing drug-like properties. The most potent derivative exhibited an EC50 value of 1.5±0.2 µM and 37±2% maximum relative FXR activation. We investigated its SAR regarding polar interactions with the receptor by generating derivatives and computational docking.


Assuntos
Receptores Citoplasmáticos e Nucleares/metabolismo , ortoaminobenzoatos/metabolismo , Sítios de Ligação , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Receptores Citoplasmáticos e Nucleares/agonistas , Relação Estrutura-Atividade , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química
13.
Expert Opin Ther Pat ; 23(2): 233-67, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23289354

RESUMO

INTRODUCTION: Prostaglandins and their G-protein-coupled receptors play numerous physiological and pathophysiological roles, especially in inflammation and its resolution. The variety of effects mediated by prostanoids makes prostanoid receptors valuable drug targets and the research on prostaglandin receptor modulators is intensive. The physiological and pathophysiological effects of prostaglandin E(2) are especially complex and numerous. The four subtypes of EP receptor have gained a lot of industrial and academic interest, in particular EP(2) and EP(4) for various indications. AREAS COVERED: Evaluation of the patent activity over the last decade (2002 - 2012) illustrates several potent compounds targeting the distinct prostaglandin E(2) receptors. Many novel methods for the use of EP receptor modulators have been developed, in addition to the classical indications for agents modulating the arachidonic acid cascade such as pain and inflammation. EXPERT OPINION: Several EP targeting agents with good potency and selectivity have been developed but their pharmacological use and utility has not yet been satisfactorily investigated. More research is necessary, and clinical use of these agents might therefore take some more time.


Assuntos
Desenho de Drogas , Patentes como Assunto , Receptores de Prostaglandina E/efeitos dos fármacos , Animais , Dinoprostona/metabolismo , Humanos , Estrutura Molecular , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP1/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP1/metabolismo , Receptores de Prostaglandina E Subtipo EP2/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP3/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP3/metabolismo , Receptores de Prostaglandina E Subtipo EP4/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Expert Opin Ther Pat ; 23(1): 47-77, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23151189

RESUMO

INTRODUCTION: Prostaglandins and their G-protein coupled receptors play numerous physiological and pathophysiological roles especially in inflammation and its resolution. The variety of physiological effects mediated by prostanoids makes prostanoid receptors valuable drug targets and the research on prostaglandin receptor modulators is intensive. Prostaglandin receptor targeting drugs might be beneficial for the treatment of inflammatory, allergic, respiratory and cardiovascular disorders as well as treatment of pain but several novel fields of use such as cancer and ophthalmic diseases have also been found apart from these classical indications. AREAS COVERED: Evaluation of the patent activity over the last decade (2002 - 2012) illustrates many potent and selective modulators of the distinct prostanoid receptors and some novel methods for their use besides the classical indications. By now, some prostaglandin receptor antagonists already have reached clinical development. EXPERT OPINION: Though the structural diversity of compounds targeting prostanoid receptors is not really large, several highly potent agents with favorable properties have been developed. The clinical potential of FP, IP, TP and DP modulators remains to be investigated, while first very promising clinical results are available as far as CRTH2 is concerned.


Assuntos
Desenho de Drogas , Prostaglandinas/metabolismo , Receptores de Prostaglandina/efeitos dos fármacos , Animais , Humanos , Terapia de Alvo Molecular , Patentes como Assunto , Receptores de Prostaglandina/metabolismo
15.
J Med Chem ; 55(23): 10771-5, 2012 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-23130964

RESUMO

Metabolic syndrome is a complex condition which often requires the use of multiple medications as a treatment. The resulting problems of polypharmacy are increase in side effects, drug-drug interactions, and its high economic cost. Development of multitarget compounds is a promising strategy to avoid the complications arising from administration of multiple drugs. Modulators of peroxisome proliferator-activated receptors (PPARs) are established agents in the treatment of dyslipidaemia, hyperglycaemia, and insulin resistance. Inhibitors of soluble epoxide hydrolase (sEH) are under evaluation for their use in cardiovascular diseases. In the present study, a series of dual sEH/PPAR modulators containing a pyrrole acidic headgroup and a urea pharmacophore were designed, synthesized, and evaluated in vitro using recombinant enzyme and cell-based assays. Compounds with different activity profiles were obtained which could be used in the treatment of metabolic syndrome.


Assuntos
Epóxido Hidrolases/síntese química , Receptores Ativados por Proliferador de Peroxissomo/química , Cromatografia Líquida de Alta Pressão , Interações de Medicamentos , Epóxido Hidrolases/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Solubilidade
16.
Expert Opin Ther Pat ; 22(7): 803-41, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22697317

RESUMO

INTRODUCTION: Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. The three known subtypes PPARα, PPARγ and PPARδ have different tissue distribution and play a key role as regulators of glucose and lipid homeostasis as well as in cell proliferation, differentiation and inflammatory responses. They have gained a lot of interest as pharmaceutical targets over the last years and with the antidiabetic thiazolidindiones (TZDs) and the hypolipidemic fibrates, two classes of drugs had entered the market. Early observations of severe adverse events changed the situation in the recent past. AREAS COVERED: Herein the authors summarize recent (2008-present) patent applications concerning PPAR ligands claimed for the use in metabolic disorders as well as patents indicating new applications for modulators of the PPAR subtypes. EXPERT OPINION: Looking at the recent patent activity regarding novel compounds, there have not been real innovations. As major applications for therapeutic PPAR ligands cancer therapy, skin-related disorders and systemic anti-inflammatory therapies might arise in the mid-term future. The known PPAR targeting drugs might see a repurposing for novel indications.


Assuntos
PPAR alfa/efeitos dos fármacos , PPAR delta/efeitos dos fármacos , PPAR gama/efeitos dos fármacos , Animais , Sistemas de Liberação de Medicamentos , Desenho de Drogas , Humanos , Ligantes , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/fisiopatologia , PPAR alfa/metabolismo , PPAR delta/metabolismo , PPAR gama/metabolismo , Patentes como Assunto
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