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1.
Expert Opin Investig Drugs ; 29(2): 197-204, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31948295

RESUMO

Introduction: Fibroblast growth factor (FGF) 21 is a member of the FGF19 sub-family of signaling molecules. They have been found to act at the localized paracrine/autocrine and systemic endocrine levels because of their extracellular matrix and co-receptor protein binding characteristics. While the molecule circulates systemically, it has specificity conferred by a co-factor binding protein ß-Klotho which is preferentially expressed in hepatic and adipose tissues. This protein, in conjunction with the FGF receptor (FGFR), propagates the downstream effects of the growth factor signaling cascade, which has been linked to fat and glucose metabolism. FGF21 has been recognized as a possible pathway for the treatment of nonalcoholic fatty liver disease (NAFLD). Targeting of the FGF21/FGFR/ß-Klotho pathway may halt or reverse hepatic fat infiltration, inflammation, and fibrosis.Areas covered: This article summarizes preclinical and clinical data on the efficacy and safety of two FGF21 agonist therapies in development.Expert opinion: Preclinical and clinical data justify further investigation of FGF21 agonist therapies for the treatment of NAFLD. However, issues including injection site reactions and possible effects on bone homeostasis mean that safety must be evaluated carefully.


Assuntos
Desenvolvimento de Medicamentos , Fatores de Crescimento de Fibroblastos/agonistas , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais
2.
Expert Opin Investig Drugs ; 29(2): 179-190, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31948298

RESUMO

Introduction: Globally, deaths from liver disease are increasing and for most patients there are few curative options. Fibrosis or scarring is often associated with the formation and progression of liver disease; however, clinical anti-fibrotic therapies are lacking. Recent work has shown that Wnt signaling, a signaling pathway that is necessary for embryonic development and cancer, can also regulate scar formation in the liver.Areas covered: This article seeks to shed light on the dualistic role of Wnt signaling in liver regeneration following injury and how Wnt signaling can regulate scar formation. It also discusses how Wnt signaling cooperates with other classical fibrogenic signaling cascades, such as TGFß signaling. Finally, the article examines recent advances in the development of Wnt signaling pathway inhibitors and asks whether repurposing these agents as anti-fibrotic therapies is a realistic option.Expert opinion: The understanding of Wnt signaling in liver regeneration and fibrosis is in its infancy and whilst new generations of Wnt pathway inhibitors have shown anti-fibrotic effects, further research is necessary to enhance our understanding of the Wnt-landscape in different patterns of liver disease. This will accelerate the development of more specific Wnt inhibitor-based anti-fibrotics.


Assuntos
Cirrose Hepática/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Cicatriz/prevenção & controle , Progressão da Doença , Desenvolvimento de Medicamentos , Humanos , Cirrose Hepática/fisiopatologia , Hepatopatias/fisiopatologia , Regeneração Hepática/efeitos dos fármacos
10.
Expert Opin Investig Drugs ; 29(2): 191-196, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31928475

RESUMO

Introduction: NASH and type 2 diabetes (T2D) are clinical definitions that overlap and result from metabolic dysfunction caused by over-nutrition relative to metabolic need. This volume details drug development programs aimed at specific NASH pathology with a focus on liver outcomes; this commentary suggests a metabolic approach that should not be overlooked based on a new understanding of insulin sensitizers.Areas covered: The overlap of NASH and T2D with respect to metabolic syndrome is discussed in the context of new understandings of insulin sensitizers. Adverse clinical outcomes in subjects with advanced NAFLD (e.g. NASH) and advanced metabolic dysfunction (e.g., T2D) are primarily due to cardiovascular issues. Clinical evidence suggests that insulin resistance and hyperinsulinemia predict adverse cardiovascular outcomes. NALFD/NASH significantly contributes to insulin resistance and hyperinsulinemia. A new insulin sensitizer that targets the newly identified mitochondrial pyruvate carrier could provide an approach.Expert opinion: A metabolic approach is needed for the treatment of NASH. Clinical studies are underway to determine whether a new insulin sensitizer that targets pyruvate metabolism can impact NASH, T2D, and cardiovascular disease. A broader view of metabolic disease may provide a more assessable way to track therapeutic benefit.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Desenvolvimento de Medicamentos , Humanos , Resistência à Insulina , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/fisiopatologia , Múltiplas Afecções Crônicas , Hepatopatia Gordurosa não Alcoólica/fisiopatologia
11.
Expert Opin Drug Metab Toxicol ; 16(1): 11-30, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31903790

RESUMO

Introduction: Chemokine receptors are important therapeutic targets for the treatment of many human diseases. This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.Areas covered: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.Expert opinion: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.


Assuntos
Desenvolvimento de Medicamentos , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Humanos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Receptores CCR4/antagonistas & inibidores , Receptores CCR4/metabolismo , Receptores CCR5/efeitos dos fármacos , Receptores CCR5/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Receptores de Quimiocinas/metabolismo
13.
Expert Opin Ther Pat ; 30(1): 1-13, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31825687

RESUMO

Introduction: Peroxisome proliferator-activated receptors (PPARs), PPARα, PPARδ, and PPARγ, play an important role in the regulation of various physiological processes, specifically lipid and energy metabolism and immunity. PPARα agonists (fibrates) and PPARγ agonists (thiazolidinediones) are used for the treatment of hypertriglyceridemia and type 2 diabetes, respectively. PPARδ activation enhances mitochondrial and energy metabolism but PPARδ-acting drugs are not yet available. Many synthetic ligands for PPARs have been developed to expand their therapeutic applications.Areas covered: The authors searched recent patent activity regarding PPAR ligands. Novel PPARα agonists, PPARδ agonists, PPARγ agonists, PPARα/γ dual agonists, and PPARγ antagonists have been claimed for the treatment of metabolic disease and inflammatory disease. Methods for the combination of PPAR ligands with other drugs and expanded application of PPAR agonists for bone and neurological disease have been also claimed.Expert opinion: Novel PPAR ligands and the combination of PPAR ligands with other drugs have been claimed for the treatment of mitochondrial disease, inflammatory/autoimmune disease, neurological disease, and cancer in addition to metabolic diseases including dyslipidemia and type 2 diabetes. Selective therapeutic actions of PPAR ligands should be exploited to avoid adverse effects. More basic studies are needed to elucidate the molecular mechanisms of selective actions.


Assuntos
PPAR alfa/metabolismo , PPAR delta/metabolismo , PPAR gama/metabolismo , Animais , Desenvolvimento de Medicamentos , Humanos , Ligantes , PPAR alfa/agonistas , PPAR alfa/antagonistas & inibidores , PPAR delta/agonistas , PPAR delta/antagonistas & inibidores , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , Patentes como Assunto
14.
Expert Opin Ther Pat ; 30(1): 27-38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31771391

RESUMO

Introduction: The activation of free fatty acid receptor 1 (FFAR1) induces insulin secretion in a glucose-dependent manner, and thereby is considered as an attractive anti-diabetic target. The clinical studies provided a lot of evidence that FFAR1 agonists improved glucose control in T2DM without the risk of hypoglycemia. The field of FFAR1 agonists is extremely competitive with many patent applications filed in recent years identifying potent candidates.Area covered: The present review summarizes patent applications (2016-2019) filing for FFAR1 modulators, including FFAR1 partial/full agonists, atypical agonists, and multiple target agonists, along with in vitro and in vivo evaluation.Expert opinion: The clinical studies of FFAR1 agonists have proved their potential for the improvement of glucose control. However, there are a few issues still to be solved in this field since TAK-875 terminated in Phase III studies due to liver toxicity. The biggest challenge on the development of FFAR1 agonists may not be the identification of a highly potent compound, but finding out the exact mechanisms of hepatotoxicity and avoid it. Moreover, the further exploration of chemical spaces on FFAR1 full agonists and multi-targeted agonists, as well as corresponding clinical studies, will be expected and might open up new directions in this field.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Benzofuranos/efeitos adversos , Benzofuranos/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Desenvolvimento de Medicamentos , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Patentes como Assunto , Receptores Acoplados a Proteínas-G/metabolismo , Sulfonas/efeitos adversos , Sulfonas/farmacologia
15.
Expert Opin Investig Drugs ; 29(1): 5-14, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31815551

RESUMO

Introduction: Kinesin spindle protein (KSP) is indispensable for the proper separation of spindle poles during mitosis. Importantly, this protein is expressed only in cells undergoing cell division and hence represents an appealing target for the treatment of cancer. Many KSP inhibitors have demonstrated a strong antitumoral effect in vitro, however, they have exhibited only limited activity in clinical trials. By contrast, the KSP inhibitor filanesib has demonstrated clinical efficacy in patients with multiple myeloma (MM).Areas covered: This article provides a comprehensive overview about the progress to date in the preclinical and clinical development of filanesib for the treatment of cancer, and particularly, MM.Expert opinion: Responses observed with filanesib alone or in combination with dexamethasone were encouraging in MM. However, the subsequent appearance of highly effective novel agents such as monoclonal antibodies, has hindered the development of agents such as filanesib that exhibit a more limited activity. Nevertheless, filanesib has shown interesting results for some patients when combined with carfilzomib and pomalidomide. Most importantly, the availability of a biomarker of response such as alpha 1-acid glycoprotein (AAG), could be key to the identification of patients that could benefit most from these combinations.


Assuntos
Antimitóticos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Tiadiazóis/administração & dosagem , Animais , Antimitóticos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/metabolismo , Desenvolvimento de Medicamentos , Humanos , Cinesina/antagonistas & inibidores , Mieloma Múltiplo/patologia , Tiadiazóis/farmacologia
16.
Expert Opin Ther Pat ; 30(1): 57-81, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31815566

RESUMO

Introduction: The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, functions as an 'epigenetic reader' that binds to acetylated lysine (KAc) residues on histone tails sophisticatedly regulating chromatin structure and gene expression. Recently, emerging evidence demonstrates that BRD4 plays a significant role in the occurrence and progression of several malignant human diseases especially cancers, making it a hot target in cancer therapy.Areas covered: This review mainly summarizes the patents of BRD4 inhibitors that have been authorized from 2013 to 2019. The patents are mostly described in terms of chemical structures, molecular mechanisms of action, pharmacological activities and potential clinical applications, including combination therapies. The development of BRD4 inhibitors in the clinical phase has been highlighted. Prospects for further development of more selective BRD4 inhibitors are provided.Expert opinion: In 2013-2019, several previously known chemical scaffolds have been further developed and disclosed. Although many small molecule BRD4 inhibitors with high potency and diverse scaffolds have been developed, the selectivity of most BRD4 inhibitors still needs to be improved. Therefore, the development of more selective small molecule inhibitors or combined use of drugs such as immunotherapy may provide new ideas for drug development.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fatores de Transcrição/antagonistas & inibidores , Animais , Proteínas de Ciclo Celular/metabolismo , Desenvolvimento de Medicamentos , Humanos , Neoplasias/patologia , Patentes como Assunto , Fatores de Transcrição/metabolismo
17.
Expert Opin Drug Saf ; 19(1): 19-22, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31739696

RESUMO

Introduction: The 18th Annual Meeting of the Safety Pharmacology Society included a session dedicated to the assessment of drug safety on the gastrointestinal (GI) system.Areas covered: GI anatomy, physiology, adverse effects (AEs) of chemical and biological therapies, and approaches to mitigate them.Expert opinion: GI AEs, albeit common and generally of minor intensity, may prolong clinical development time and reduce patient compliance.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Gastroenteropatias/induzido quimicamente , Trato Gastrointestinal/efeitos dos fármacos , Animais , Desenvolvimento de Medicamentos/métodos , Humanos
18.
Expert Opin Investig Drugs ; 29(1): 63-71, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31847611

RESUMO

Introduction: Obesity is compounded by a neurobiology that is resistant to weight loss. Therefore, the development of pharmacotherapies to address the pathology underlying the dysregulation of energy homeostasis is critical.Areas covered: This review examines selected clinical trial evidence for the pharmacologic treatment of obesity and provides an expert opinion on anti-obesity drug development. The article includes the outcomes of anti-obesity medications that have been evaluated in clinical trials but have not yet received approval from the U.S. Food and Drug Administration. The mechanisms of action of glucagon-like peptide-1 agonists and co-agonists, diabetes medications being investigated for weight loss, and medications acting on the central nervous system as well as peripherally are reviewed. A search was conducted on PubMed using the terms 'Obesity AND Medications' restricted to clinical trials reported in English. Using similar terms, a search was also conducted on ClinicalTrials.gov.Expert opinion: The goal of anti-obesity therapy is finding compounds that are effective and have minimal side effects. Combining medications targeting more than one of the redundant mechanisms driving obesity increases efficacy. However, targeting peripheral mechanisms to overcome the trickle-down effects of centrally acting drugs may be the key to success in treating obesity.


Assuntos
Fármacos Antiobesidade/administração & dosagem , Desenvolvimento de Medicamentos , Obesidade/tratamento farmacológico , Animais , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/farmacologia , Metabolismo Energético/fisiologia , Humanos , Obesidade/fisiopatologia , Perda de Peso/efeitos dos fármacos
19.
Expert Opin Ther Pat ; 30(2): 87-101, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31854208

RESUMO

Introduction: The chemokine receptor CXCR4 has been under intense study due to the central role it plays in immune system regulation and the pathology of many human diseases. The FDA approval of the first CXCR4 antagonist drug Plerixafor (i.e. AMD3100, Mozobil®) ushered in an increase in patent activity covering CXCR4 based therapeutic agents over the past decade.Areas covered: This article describes patent documents published during the period of 2010 through 2018 for both small molecules and peptide-based CXCR4 modulators as therapeutic agents. There is an expansion of intellectual property (IP) around existing and new small molecules of clinical interest, including new chemotypes featuring aromatic and aliphatic heterocycles. There is also significant IP covering peptide-based therapeutics, although about half as many in number as those covering small molecules.Expert opinion: In the last decade there has been significant interest in modulators of the CXCR4 receptor, as gauged by the number of patent filings and clinical investigations targeting this receptor for human disease intervention. Seven of the many CXCR4 modulators described herein, that are currently in human clinical trials, are likely to spur the creation of other FDA approved therapeutics in the near future, most likely as immune and oncology drugs.


Assuntos
Desenvolvimento de Medicamentos , Peptídeos/farmacologia , Receptores CXCR4/efeitos dos fármacos , Animais , Compostos Heterocíclicos/farmacologia , Humanos , Patentes como Assunto , Receptores CXCR4/metabolismo
20.
Expert Opin Ther Pat ; 30(2): 137-145, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31865810

RESUMO

Introduction: The greater interest in TAAR1-mediated potential for the treatment of different pathologies, especially those related to CNS disorders, has given a considerable boost to the search for developing TAAR1-selective small molecules.Areas covered: During the last decade, the medicinal chemistry efforts have allowed the yield of various chemotypes to be properly dressed toward TAAR1 receptor. The more relevant chemical features and structure-activity relationship studies on the TAAR1 ligands will be discussed in order to guide future drug discovery investigations.Expert opinion: The discovery of TAAR receptors has allowed better investigation of the role played by TAs, not only as secondary neuromodulators, but also as neurotransmitters, even if it should still be completely clarified. This has drawn new ways for further insights around the TAAR1 involvement in numerous diseases. Despite this, the limited number of promising ligands targeting hTAAR1 orthologue makes the discovery of novel compounds still a challenging task. Relevant efforts have to be focused on safe ligands, devoid of any side-efficacy toward other highly related GPCR (monoaminergic systems). Moreover, species-specificity preferences experienced by numerous compounds so far investigated, based on rodent models and translated to the human environment, turn in a critical bottleneck in drug discovery.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Desenvolvimento de Medicamentos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Animais , Doenças do Sistema Nervoso Central/fisiopatologia , Descoberta de Drogas , Humanos , Ligantes , Patentes como Assunto , Receptores Acoplados a Proteínas-G/metabolismo , Relação Estrutura-Atividade
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