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1.
JCI Insight ; 6(8)2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33724959

RESUMO

Nephrogenic diabetes insipidus (NDI) patients produce large amounts of dilute urine. NDI can be congenital, resulting from mutations in the type-2 vasopressin receptor (V2R), or acquired, resulting from medications such as lithium. There are no effective treatment options for NDI. Activation of PKA is disrupted in both congenital and acquired NDI, resulting in decreased aquaporin-2 phosphorylation and water reabsorption. We show that adenosine monophosphate-activated protein kinase (AMPK) also phosphorylates aquaporin-2. We identified an activator of AMPK, NDI-5033, and we tested its ability to increase urine concentration in animal models of NDI. NDI-5033 increased AMPK phosphorylation by 2.5-fold, confirming activation. It increased urine osmolality in tolvaptan-treated NDI rats by 30%-50% and in V2R-KO mice by 50%. Metformin, another AMPK activator, can cause hypoglycemia, which makes it a risky option for treating NDI patients, especially children. Rats with NDI receiving NDI-5033 showed no hypoglycemia in a calorie-restricted, exercise protocol. Congenital NDI therapy needs to be effective long-term. We administered NDI-5033 for 3 weeks and saw no reduction in efficacy. We conclude that NDI-5033 can improve urine concentration in animals with NDI and holds promise as a potential therapy for patients with congenital NDI due to V2R mutations.


Assuntos
Adenilato Quinase/efeitos dos fármacos , Diabetes Insípido Nefrogênico/metabolismo , Ativadores de Enzimas/farmacologia , Capacidade de Concentração Renal/efeitos dos fármacos , Adenilato Quinase/metabolismo , Animais , Aquaporina 2/metabolismo , Diabetes Insípido Nefrogênico/genética , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Receptores de Vasopressinas/genética
2.
J Pain Res ; 8: 859-70, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26672499

RESUMO

Despite proven clinical utility, buprenorphine has not been used widely for the treatment of chronic pain. Questions about "ceiling effect" or bell-shaped curve observed for analgesia in preclinical studies and potential withdrawal issues on combining with marketed µ-agonists continue to hinder progress in expanding full potential of buprenorphine in the treatment of cancer and noncancer pain. Mounting evidence from clinical studies and conclusions drawn by a panel of experts strongly support superior safety and efficacy profile of buprenorphine vs marketed opioids. No ceiling on analgesic effect has been reported in clinical studies. The receptor pharmacology and pharmacokinetics profile of buprenorphine is complex but unique and contributes to its distinct safety and efficacy. The buprenorphine pharmacology also allows it to be combined with other µ-receptor opioids for additivity in efficacy. Transdermal delivery products of buprenorphine have been preferred choices for the management of pain but new delivery options are under investigation for the treatment of both opioid dependence and chronic pain.

3.
Drug Discov Today ; 20(11): 1382-90, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26259523

RESUMO

Both neuronal and non-neuronal mechanisms have been proposed to contribute to neuropathic pain (NP). All currently approved treatments for NP modulate neuronal targets and provide only symptomatic relief. Here we review evidence that inhibition of soluble epoxide hydrolase (sEH), the enzyme that degrades epoxyeicosatrienoic acids (EETs), has potential to be a multimodal, disease modifying approach to treat NP: (1) EET actions involve both endogenous opioid system and the GABAergic systems thus provide superior pain relief compared to morphine or gabapentin, (2) EETs are directly anti-inflammatory and inhibit expression of inflammatory cytokines and adhesion molecules thus can prevent continued nerve damage; and (3) EETs promote nerve regeneration in cultured neurons. Thus, an sEH inhibitor will not only provide effective pain relief, but would also block further nerve damage and promote healing.


Assuntos
Analgésicos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Neuralgia/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Desenho de Fármacos , Eicosanoides/metabolismo , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/metabolismo , Humanos , Neuralgia/enzimologia , Neuralgia/fisiopatologia
4.
Bioorg Med Chem Lett ; 25(4): 887-92, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25599839

RESUMO

Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.


Assuntos
Benzimidazóis/farmacologia , Receptores Opioides kappa/agonistas , Sequência de Aminoácidos , Simulação por Computador , Humanos , Dados de Sequência Molecular , Receptores Opioides kappa/química , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade
5.
Drug Discov Today ; 17(19-20): 1088-102, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22627006

RESUMO

Low productivity, rising R&D costs, dissipating proprietary products and dwindling pipelines are driving the pharmaceutical industry to unprecedented challenges and scrutiny. In this article I reflect on the current status of the pharmaceutical industry and reasons for continued low productivity. An emerging 'symbiotic model of innovation', that addresses underlying issues in drug failure and attempts to narrow gaps in current drug discovery processes, is discussed to boost productivity. The model emphasizes partnerships in innovation to deliver quality products in a cost-effective system. I also discuss diverse options to build a balanced research portfolio with higher potential for persistent delivery of drug molecules.


Assuntos
Descoberta de Drogas , Indústria Farmacêutica/tendências , Animais , Comportamento Cooperativo , Eficiência , Humanos
6.
Bioorg Med Chem Lett ; 22(9): 3163-7, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22497763

RESUMO

Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.


Assuntos
Desenho de Fármacos , Quinazolinas/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Doenças Cardiovasculares/prevenção & controle , Humanos , Quinazolinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 22(9): 3157-62, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22487182

RESUMO

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the ß2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.


Assuntos
Desenho de Fármacos , Quinazolinas/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Humanos , Estrutura Molecular , Quinazolinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Relação Estrutura-Atividade
8.
Inflamm Allergy Drug Targets ; 11(2): 143-58, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22280237

RESUMO

Chronic inflammation is an important contributing factor to a variety of human diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis and atherosclerosis. Epoxidation of arachidonic acid by cytochrome P450 enzymes during inflammation yields epoxyeicosatrienoic acids (EETs). EETs have a variety of biological effects including modulation of inflammation, vascular smooth muscle migration and platelet aggregation. The EETs levels are regulated by soluble epoxide hydrolase (sEH), the major enzyme responsible for their degradation and conversion to inactive dihydroxyeicosatrienoic acids (DHETs); thereby limiting many of the biological actions of EETs. The molecular and pharmacological inhibition of sEH has been studied extensively for benefits on the cardiovascular system. More recent studies suggest the importance of EETs and sEH in pain and inflammation. This review will discuss the current status and emerging evidence on the role of sEH and sEH inhibitors in chronic inflammatory conditions such as atherosclerosis, colitis and arthritis. Although steroids and non-steroidal anti-inflammatory drugs are effective, their chronic use is limited by the metabolic and cardiovascular side effects. Currently there are no small molecule drugs for treatment of chronic inflammation and associated pain and sEH inhibitors with their intrinsic cardiovascular protective effects can potentially fill this void.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Inflamação/tratamento farmacológico , Terapia de Alvo Molecular , Dor/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Ácido Araquidônico/metabolismo , Aterosclerose/enzimologia , Doenças Autoimunes/enzimologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Domínio Catalítico , Desenho de Fármacos , Ácidos Eicosanoicos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Ratos
9.
CNS Neurol Disord Drug Targets ; 10(5): 545-58, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21631410

RESUMO

Fatty acid amide hydrolase (FAAH) is responsible for hydrolysis of endocannabinoid, anandamide (AEA), and N-acyl ethanolamines such as palmitoylethanolamine (PEA) and N-oleoylethanolamide (OEA). Genetic deletion or pharmacological inactivation of FAAH shows site-specific elevation of AEA that plays a role in the modulation of pain and other neurodegenerative disorders. The review elaborates recent progress and current status of diverse structural classes of reversible and irreversible FAAH inhibitors. The discussion also addresses ligand-enzyme active site interactions and mechanism of enzyme inactivation, emerging approaches to novel FAAH inhibitors, and ongoing efforts to address gaps in therapeutic utility of FAAH inhibitors.


Assuntos
Amidoidrolases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Amidoidrolases/química , Amidoidrolases/fisiologia , Animais , Ácidos Araquidônicos/fisiologia , Moduladores de Receptores de Canabinoides/metabolismo , Canabinoides/antagonistas & inibidores , Canabinoides/química , Canabinoides/metabolismo , Canabinoides/farmacologia , Endocanabinoides , Inibidores Enzimáticos/uso terapêutico , Etanolaminas/farmacologia , Etanolaminas/uso terapêutico , Humanos , Hidrólise , Ácidos Oleicos/farmacologia , Ácidos Oleicos/uso terapêutico , Alcamidas Poli-Insaturadas
11.
Drug Discov Today ; 14(23-24): 1098-111, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19716430

RESUMO

Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of several important endogenous fatty acid amides (FAAs), including anandamide, oleoylethanolamide and palmitoylethanolamide. Because specific FAAs interact with cannabinoid and vanilloid receptors, they are often referred to as 'endocannabinoids' or 'endovanilloids'. Initial interest in this area, therefore, has focused on developing FAAH inhibitors to augment the actions of FAAs and reduce pain. However, recent literature has shown that these FAAs - through interactions with unique receptors (extracellular and intracellular) - can induce a diverse array of effects that include appetite suppression, modulation of lipid and glucose metabolism, vasodilation, cardiac function and inflammation. This review gives an overview of FAAs and diverse FAAH inhibitors and their potential therapeutic utility in pain and non-pain indications.


Assuntos
Amidas/metabolismo , Amidoidrolases/antagonistas & inibidores , Moduladores de Receptores de Canabinoides/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Ácidos Graxos/metabolismo , Doenças Metabólicas/tratamento farmacológico , Dor/tratamento farmacológico , Animais , Doenças Cardiovasculares/metabolismo , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Dor/metabolismo , Receptores de Canabinoides/metabolismo
12.
Bioorg Med Chem ; 15(10): 3390-412, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17387018

RESUMO

The integrin alpha(v)beta(3) is expressed in a number of cell types and is thought to play a major role in several pathological conditions. Various small molecules that inhibit the integrin have been shown to suppress tumor growth and retinal angiogenesis. The tripeptide Arg-Gly-Asp (RGD), a common binding motif in several ligands that bind to alpha(v)beta(3), has been depeptidized and optimized in our efforts toward discovering a small molecule inhibitor. We recently disclosed the synthesis and biological activity of several small molecules that did not contain any peptide bond and mimic the tripeptide RGD. The phenethyl group in one of the lead compounds was successfully replaced with a cyclopropyl moiety. The new lead compound was optimized for potency, selectivity, and for its ADME properties. We describe herein the discovery, synthesis, and optimization of cyclopropyl containing analogs that are potent and selective inhibitors of alpha(v)beta(3).


Assuntos
Acetatos/síntese química , Acetatos/farmacologia , Integrina alfaVbeta3/antagonistas & inibidores , Naftiridinas/síntese química , Naftiridinas/farmacologia , Animais , Área Sob a Curva , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Desenho de Fármacos , Meia-Vida , Humanos , Indicadores e Reagentes , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , Transfecção
13.
Bioorg Med Chem Lett ; 16(4): 839-44, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16298127

RESUMO

We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6.


Assuntos
Butiratos/síntese química , Butiratos/farmacologia , Integrina alfaVbeta3/antagonistas & inibidores , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Antígenos de Neoplasias , Butiratos/química , Linhagem Celular , Humanos , Integrinas/antagonistas & inibidores , Estrutura Molecular , Oxidiazóis/química , Receptores de Vitronectina/antagonistas & inibidores , Relação Estrutura-Atividade
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