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1.
J Headache Pain ; 23(1): 79, 2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35799128

RESUMO

Targeting fatty acid amide hydrolase (FAAH) is a promising therapeutic strategy to combat certain forms of pain, including migraine headache. FAAH inhibitors, such as the O-biphenyl-3-yl carbamate URB597, have been shown to produce anti-hyperalgesic effects in animal models of migraine. The objective of this study was to investigate the behavioral and biochemical effects of compounds ARN14633 and ARN14280, two URB597 analogs with improved solubility and bioavailability, in a migraine-specific rat model in which trigeminal hyperalgesia is induced by nitroglycerin (NTG) administration. ARN14633 (1 mg/kg, i.p.) and ARN14280 (3 mg/kg, i.p.) were administered to adult male Sprague-Dawley rats 3 hours after NTG injection. One hour after the administration of either compound, rats were subjected to the orofacial formalin test. ARN14633 and ARN14280 attenuated NTG-induced nocifensive behavior and reduced transcription of genes encoding neuronal nitric oxide synthase, pain mediators peptides (calcitonin gene-related peptide, substance P) and pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta and 6) in the trigeminal ganglion, cervical spinal cord and medulla. Finally, both compounds strongly elevated levels of endocannabinoids and/or other FAAH substrates in cervical spinal cord and medulla, and, to a lesser extent, in the trigeminal ganglia. The results indicate that the novel global FAAH inhibitors ARN14633 and ARN14280 elicit significant anti-hyperalgesic effects in a migraine-specific animal model and inhibit the associated peptidergic-inflammatory response. Although the precise mechanism underlying these effects remains to be elucidated, our results support further investigational studies of FAAH blockade as a potential therapeutic strategy to treat migraine conditions.


Assuntos
Endocanabinoides , Transtornos de Enxaqueca , Amidas/efeitos adversos , Amidoidrolases/genética , Amidoidrolases/uso terapêutico , Animais , Modelos Animais de Doenças , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Masculino , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/tratamento farmacológico , Nitroglicerina/farmacologia , Dor , Ratos , Ratos Sprague-Dawley
2.
Anal Chem ; 88(19): 9510-9517, 2016 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-27583774

RESUMO

We propose a new QSRR model based on a Kernel-based partial least-squares method for predicting UPLC retention times in reversed phase mode. The model was built using a combination of classical (physicochemical and topological) and nonclassical (fingerprints) molecular descriptors of 1383 compounds, encompassing different chemical classes and structures and their accurately measured retention time values. Following a random splitting of the data set into a training and a test set, we tested the ability of the model to predict the retention time of all the compounds. The best predicted/experimental R2 value was higher than 0.86, while the best Q2 value we observed was close to 0.84. A comparison of our model with traditional and simpler MLR and PLS regression models shows that KPLS better performs in term of correlation (R2), prediction (Q2), and support to MetID peak assignment. The KPLS model succeeded in two real-life MetID tasks by correctly predicting elution order of Phase I metabolites, including isomeric monohydroxylated compounds. We also show in this paper that the model's predictive power can be extended to different gradient profiles, by simple mathematical extrapolation using a known equation, thus offering very broad flexibility. Moreover, the current study includes a deep investigation of different types of chemical descriptors used to build the structure-retention relationship.


Assuntos
Cromatografia Líquida , Modelos Químicos , Algoritmos , Análise dos Mínimos Quadrados , Análise de Componente Principal
3.
Anal Biochem ; 495: 52-9, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26686030

RESUMO

Nuclear magnetic resonance (NMR)-based screening has been recognized as a powerful approach for the identification and characterization of molecules interacting with pharmaceutical targets. Indeed, several NMR methods have been developed and successfully applied to many drug discovery projects. Whereas most of these approaches have targeted isolated biomolecular receptors, very few cases are reported with the screening performed in intact cells and cell extracts. Here we report the first successful application of the fluorine NMR-based assay n-FABS (n-fluorine atoms for biochemical screening) in living mammalian cells expressing the membrane protein fatty acid amide hydrolase (FAAH). This method allows the identification of both weak and potent inhibitors and the measurement of their potency in a physiological environment.


Assuntos
Amidoidrolases/análise , Ressonância Magnética Nuclear Biomolecular , Amidoidrolases/metabolismo , Benzamidas/química , Benzamidas/metabolismo , Carbamatos/química , Carbamatos/metabolismo , Flúor/química , Células HEK293 , Humanos , Concentração Inibidora 50
4.
FASEB J ; 29(6): 2616-27, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25757568

RESUMO

The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointestinal (GI) epithelium. This toxic action greatly limits the use of NSAIDs in inflammatory bowel disease (IBD) and other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide, which attenuates inflammation and promotes GI healing. Here, we describe the first class of systemically active agents that simultaneously inhibit FAAH, Cox-1, and Cox-2 with high potency and selectivity. The class prototype 4: (ARN2508) is potent at inhibiting FAAH, Cox-1, and Cox-2 (median inhibitory concentration: FAAH, 0.031 ± 0.002 µM; Cox-1, 0.012 ± 0.002 µM; and Cox-2, 0.43 ± 0.025 µM) but does not significantly interact with a panel of >100 off targets. After oral administration in mice, ARN2508 engages its intended targets and exerts profound therapeutic effects in models of intestinal inflammation. Unlike NSAIDs, ARN2508 causes no gastric damage and indeed protects the GI from NSAID-induced damage through a mechanism that requires FAAH inhibition. Multitarget FAAH/Cox blockade may provide a transformative approach to IBD and other pathologies in which FAAH and Cox are overactive.


Assuntos
Amidoidrolases/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Trato Gastrointestinal/enzimologia , Inflamação/enzimologia , Amidoidrolases/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Carragenina , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/enzimologia , Gastroenteropatias/prevenção & controle , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/patologia , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Intestinos/efeitos dos fármacos , Intestinos/enzimologia , Intestinos/patologia , Camundongos , Estrutura Molecular , Fenilcarbamatos/química , Fenilcarbamatos/farmacocinética , Fenilcarbamatos/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacologia , Fatores de Tempo , Resultado do Tratamento
5.
Angew Chem Int Ed Engl ; 55(37): 11193-11197, 2016 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-27404798

RESUMO

Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions are terminated by the intracellular cysteine amidase, N-acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti-inflammatory therapy, the lipid-like structures and reactive warheads of current NAAA inhibitors limit the use of these agents as oral drugs. A series of novel benzothiazole-piperazine derivatives that inhibit NAAA in a potent and selective manner by a non-covalent mechanism are described. A prototype member of this class (8) displays high oral bioavailability, access to the central nervous system (CNS), and strong activity in a mouse model of multiple sclerosis (MS). This compound exemplifies a second generation of non-covalent NAAA inhibitors that may be useful in the treatment of MS and other chronic CNS disorders.


Assuntos
Amidoidrolases/antagonistas & inibidores , Modelos Animais de Doenças , Endocanabinoides/farmacologia , Inibidores Enzimáticos/farmacologia , Etanolaminas/farmacologia , Esclerose Múltipla/tratamento farmacológico , Ácidos Oleicos/farmacologia , Ácidos Palmíticos/farmacologia , Administração Oral , Amidas , Amidoidrolases/metabolismo , Animais , Relação Dose-Resposta a Droga , Endocanabinoides/administração & dosagem , Endocanabinoides/química , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Etanolaminas/administração & dosagem , Etanolaminas/química , Camundongos , Estrutura Molecular , Esclerose Múltipla/metabolismo , Ácidos Oleicos/administração & dosagem , Ácidos Oleicos/química , Ácidos Palmíticos/administração & dosagem , Ácidos Palmíticos/química , Relação Estrutura-Atividade
6.
Angew Chem Int Ed Engl ; 54(5): 1578-82, 2015 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-25504761

RESUMO

Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3ß. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03±0.01) µM and (14.67±0.78) µM for BACE-1 and GSK-3ß, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/química , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Triazinas/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Barreira Hematoencefálica/metabolismo , Domínio Catalítico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Meia-Vida , Lipopolissacarídeos/toxicidade , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Simulação de Acoplamento Molecular , Óxido Nítrico Sintase Tipo II/metabolismo , Ligação Proteica , Ratos , Triazinas/metabolismo , Triazinas/farmacologia , Regulação para Cima/efeitos dos fármacos
7.
Pharmacol Res ; 87: 87-93, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24993496

RESUMO

The blood-brain barrier (BBB) is the main entry route for chemicals into the mammalian central nervous system (CNS). Two transmembrane transporters of the ATP-binding cassette (ABC) family - breast cancer resistance protein (ABCG2 in humans, Abcg2 in rodents) and P-glycoprotein (ABCB1 in humans, Abcb1 in rodents) - play a key role in mediating this process. Pharmacological and genetic evidence suggests that Abcg2 prevents CNS access to a group of highly potent and selective O-arylcarbamate fatty-acid amidohydrolase (FAAH) inhibitors, which include the compound URB937 (cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester). To define structure-activity relationships of the interaction of these molecules with Abcg2, in the present study we tested various peripherally restricted and non-restricted O-arylcarbamate FAAH inhibitors for their ability to serve as transport substrates in monolayer cultures of Madin-Darby Canine Kidney-II (MDCKII) cells over-expressing Abcg2. Surprisingly, we found that the majority of compounds tested - even those able to enter the CNS in vivo - were substrates for Abcg2 in vitro. Additional experiments in MDCKII cells overexpressing ABCB1 revealed that only those compounds that were dual substrates for ABCB1 and Abcg2 in vitro were also peripherally restricted in vivo. The extent of such restriction seems to depend upon other physicochemical features of the compounds, in particular the polar surface area. Consistent with these in vitro results, we found that URB937 readily enters the brain in dual knockout mice lacking both Abcg2 and Abcb1, whereas it is either partially or completely excluded from the brain of mice lacking either transporter alone. The results suggest that Abcg2 and Abcb1 act together to restrict the access of URB937 to the CNS.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Amidoidrolases/antagonistas & inibidores , Canabinoides/farmacologia , Carbamatos/farmacologia , Transportadores de Cassetes de Ligação de ATP/genética , Amidoidrolases/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Canabinoides/química , Carbamatos/química , Cães , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Knockout , Relação Estrutura-Atividade
8.
J Med Chem ; 67(1): 349-379, 2024 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-38117953

RESUMO

The autophagy process appears as a promising target for anticancer interventions. Chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are the only FDA-approved autophagy flux inhibitors. Although diverse anticancer clinical trials are providing encouraging results, several limitations associated with the need of high dosage and long-term administration of these autophagy inhibitors are also emerging. We showed that the inhibition of REV-ERB, a nuclear receptor regulating circadian rhythm and metabolism, enhances CQ-mediated cancer cell death and identified a class of dual inhibitors of autophagy and REV-ERB displaying an in vitro anticancer activity against diverse tumor cells greatly higher than CQ. Herein, we describe our lead optimization strategy that led to the identification of compound 24 as a dual autophagy and REV-ERB inhibitor, showing improved potency in blocking autophagy, enhanced toxicity against cancer cells, optimal drug-like properties, and efficacy in a mouse xenograft model of melanoma as a single anticancer agent.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Animais , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Autofagia , Morte Celular , Linhagem Celular Tumoral
9.
J Am Chem Soc ; 135(1): 22-5, 2013 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-23240907

RESUMO

In addition to inhibiting the cyclooxygenase (COX)-mediated biosynthesis of prostanoids, various widely used nonsteroidal anti-inflammatory drugs (NSAIDs) enhance endocannabinoid signaling by blocking the anandamide-degrading membrane enzyme fatty acid amide hydrolase (FAAH). The X-ray structure of FAAH in complex with the NSAID carprofen, along with site-directed mutagenesis, enzyme activity assays, and NMR analysis, has revealed the molecular details of this interaction, providing information that may guide the design of dual FAAH-COX inhibitors with superior analgesic efficacy.


Assuntos
Amidoidrolases/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/farmacologia , Carbazóis/farmacologia , Amidoidrolases/metabolismo , Anti-Inflamatórios não Esteroides/química , Sítios de Ligação/efeitos dos fármacos , Carbazóis/química , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
10.
Chembiochem ; 14(13): 1611-9, 2013 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-23918626

RESUMO

Despite the recognized importance of membrane proteins as pharmaceutical targets, the reliable identification of fragment hits that are able to bind these proteins is still a major challenge. Among different ¹9F NMR spectroscopic methods, n-fluorine atoms for biochemical screening (n-FABS) is a highly sensitive technique that has been used efficiently for fragment screening, but its application for membrane enzymes has not been reported yet. Herein, we present the first successful application of n-FABS to the discovery of novel fragment hits, targeting the membrane-bound enzyme fatty acid amide hydrolase (FAAH), using a library of fluorinated fragments generated based on the different local environment of fluorine concept. The use of the recombinant fusion protein MBP-FAAH and the design of compound 11 as a suitable novel fluorinated substrate analogue allowed n-FABS screening to be efficiently performed using a very small amount of enzyme. Notably, we have identified 19 novel fragment hits that inhibit FAAH with a median effective concentration (IC50) in the low mM-µM range. To the best of our knowledge, these results represent the first application of a ¹9F NMR fragment-based functional assay to a membrane protein.


Assuntos
Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/farmacologia , Ressonância Magnética Nuclear Biomolecular , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Flúor/química , Halogenação , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato
11.
Pharmacol Res ; 65(5): 553-63, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22420940

RESUMO

Fatty-acid amide hydrolase (FAAH) catalyzes the intracellular hydrolysis of the endocannabinoid anandamide and other bioactive lipid amides. In the present study, we conducted a comparative characterization of the effects of the newly identified brain-impermeant FAAH inhibitor, URB937 ([3-(3-carbamoylphenyl)-4-hydroxy-phenyl] N-cyclohexylcarbamate), in various rodent models of acute and persistent pain. When administered by the oral route in mice, URB937 was highly active (median effective dose, ED(50), to inhibit liver FAAH activity: 0.3mgkg(-1)) and had a bioavailability of 5.3%. The antinociceptive effects of oral URB937 were investigated in mouse models of acute inflammation (carrageenan), peripheral nerve injury (chronic sciatic nerve ligation) and arthritis (complete Freund's adjuvant). In all models, URB937 was as effective or more effective than standard analgesic and anti-inflammatory drugs (indomethacin, gabapentin, dexamethasone) and reversed pain-related responses (mechanical hyperalgesia, thermal hyperalgesia, and mechanical allodynia) in a dose-dependent manner. ED(50) values ranged from 0.2 to 10mgkg(-1), depending on model and readout. Importantly, URB937 was significantly more effective than two global FAAH inhibitors, URB597 and PF-04457845, in the complete Freund's adjuvant model. The effects of a combination of URB937 with the non-steroidal anti-inflammatory agent, indomethacin, were examined in the carrageenan and chronic sciatic nerve ligation models. Isobolographic analyses showed that the two compounds interacted synergistically to attenuate pain-related behaviors. Furthermore, URB937 reduced the number and severity of gastric lesions produced by indomethacin, while exerting no ulcerogenic effect when administered alone. The results indicate that the peripheral FAAH inhibitor URB937 is more effective than globally active FAAH inhibitors at inhibiting inflammatory pain. Our findings further suggest that FAAH and cyclooxygenase inhibitors interact functionally in peripheral tissues, to either enhance or hinder each other's actions.


Assuntos
Amidoidrolases/antagonistas & inibidores , Úlcera Gástrica/prevenção & controle , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/toxicidade , Artrite Experimental/tratamento farmacológico , Artrite Experimental/fisiopatologia , Benzamidas/farmacologia , Canabinoides/administração & dosagem , Canabinoides/farmacocinética , Canabinoides/farmacologia , Carbamatos/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Indometacina/administração & dosagem , Indometacina/toxicidade , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/fisiopatologia , Piridazinas/farmacologia , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/fisiopatologia , Ureia/análogos & derivados , Ureia/farmacologia
12.
Bioorg Med Chem Lett ; 21(15): 4422-8, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21737272

RESUMO

The Hedgehog (Hh-) signaling pathway is a key developmental pathway which controls patterning, growth and cell migration in most tissues, but evidence has accumulated showing that many human tumors aberrantly reactivate this pathway. Smoothened antagonists offer opportunities for the treatment of malignancies dependent on the Hh pathway, and the most advanced clinical candidates are demonstrating encourage initial results. A novel series of [6,5]-bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione smoothened antagonists has been identified, and the series has been extensively explored to ascertain the key detriments for activity, demonstrating that the trans-2-phenylcyclopropyl and hydantoin ring systems are critical for potency, while a variety of urea substituents can be tolerated. The combination of these optimal groups gives smoothened antagonists with activity in the low nanomolar range.


Assuntos
Antineoplásicos/química , Proteínas Hedgehog/antagonistas & inibidores , Imidazóis/química , Pirazinas/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas Hedgehog/metabolismo , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 21(15): 4429-35, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21737263

RESUMO

The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development.


Assuntos
Antineoplásicos/química , Proteínas Hedgehog/antagonistas & inibidores , Imidazóis/química , Pirazinas/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Cães , Proteínas Hedgehog/metabolismo , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Ratos , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 20(2): 488-92, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20007017

RESUMO

A potent series of substituted 2-phenyl-2H-indazole-7-carboxamides were synthesized and evaluated as inhibitors of poly (ADP-ribose) polymerase (PARP). This extensive SAR exploration culminated with the identification of substituted 5-fluoro-2-phenyl-2H-indazole-7-carboxamide analog 48 which displayed excellent PARP enzyme inhibition with IC(50)=4nM, inhibited proliferation of cancer cell lines deficient in BRCA-1 with CC(50)=42nM and showed encouraging pharmacokinetic properties in rats compared to the lead 6.


Assuntos
Amidas/síntese química , Antineoplásicos/síntese química , Azetidinas/síntese química , Inibidores Enzimáticos/síntese química , Indazóis/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases , Amidas/química , Amidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Azetidinas/química , Azetidinas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Células HeLa , Humanos , Indazóis/química , Indazóis/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Ratos , Relação Estrutura-Atividade , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
15.
J Med Chem ; 63(24): 15821-15851, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33290061

RESUMO

Acid ceramidase (AC) is a cysteine hydrolase that plays a crucial role in the metabolism of lysosomal ceramides, important members of the sphingolipid family, a diversified class of bioactive molecules that mediate many biological processes ranging from cell structural integrity, signaling, and cell proliferation to cell death. In the effort to expand the structural diversity of the existing collection of AC inhibitors, a novel class of substituted oxazol-2-one-3-carboxamides were designed and synthesized. Herein, we present the chemical optimization of our initial hits, 2-oxo-4-phenyl-N-(4-phenylbutyl)oxazole-3-carboxamide 8a and 2-oxo-5-phenyl-N-(4-phenylbutyl)oxazole-3-carboxamide 12a, which resulted in the identification of 5-[4-fluoro-2-(1-methyl-4-piperidyl)phenyl]-2-oxo-N-pentyl-oxazole-3-carboxamide 32b as a potent AC inhibitor with optimal physicochemical and metabolic properties, showing target engagement in human neuroblastoma SH-SY5Y cells and a desirable pharmacokinetic profile in mice, following intravenous and oral administration. 32b enriches the arsenal of promising lead compounds that may therefore act as useful pharmacological tools for investigating the potential therapeutic effects of AC inhibition in relevant sphingolipid-mediated disorders.


Assuntos
Ceramidase Ácida/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Oxazolona/química , Ceramidase Ácida/metabolismo , Administração Oral , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Humanos , Concentração Inibidora 50 , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos/metabolismo , Simulação de Acoplamento Molecular , Oxazolona/metabolismo , Oxazolona/farmacocinética , Solubilidade , Relação Estrutura-Atividade
16.
J Med Chem ; 63(7): 3634-3664, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32176488

RESUMO

Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m, where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher's and Krabbe's diseases. After daily intraperitoneal administration at 90 mg kg-1, 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.


Assuntos
Ceramidase Ácida/antagonistas & inibidores , Benzoxazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Administração Oral , Animais , Benzoxazóis/administração & dosagem , Benzoxazóis/síntese química , Benzoxazóis/farmacocinética , Encéfalo/metabolismo , Linhagem Celular Tumoral , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Feminino , Doença de Gaucher/enzimologia , Doença de Gaucher/metabolismo , Humanos , Leucodistrofia de Células Globoides/enzimologia , Leucodistrofia de Células Globoides/metabolismo , Masculino , Camundongos , Estrutura Molecular , Psicosina/análogos & derivados , Psicosina/metabolismo , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 18(23): 6083-7, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18930398

RESUMO

Trifluoroacetylthiophene carboxamides have recently been reported to be class II HDAC inhibitors, with moderate selectivity. Exploration of replacements for the carboxamide with bioisosteric pentatomic heteroaromatic like 1,3,4-oxadiazoles, 1,2,4-oxadiazoles and 1,3-thiazoles, led to the discovery that 2-trifluoroacetylthiophene 1,3,4-oxadiazole derivatives are very potent low nanomolar HDAC4 inhibitors, highly selective over class I HDACs (HDAC 1 and 3), and moderately stable in HCT116 cell culture.


Assuntos
Inibidores de Histona Desacetilases , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Técnicas de Química Combinatória , Desenho de Fármacos , Células HCT116 , Histona Acetiltransferases/antagonistas & inibidores , Histona Desacetilases/classificação , Humanos , Estrutura Molecular , Oxidiazóis/química , Relação Estrutura-Atividade , Tiofenos/química
19.
Bioorg Med Chem Lett ; 18(11): 3456-61, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18440229

RESUMO

The identification of class II HDAC inhibitors has been hampered by lack of efficient enzyme assays, in the preceding paper two assays have been developed to improve the efficiency of these enzymes: mutating an active site histidine to tyrosine, or by the use of a trifluoroacetamide lysine substrate, allowing screening to identify class II HDAC inhibitors. Herein, 2-trifluoroacetylthiophenes have been demonstrated to inhibit class II HDACs, resulting in the development of a series of 5-(trifluoroacetyl)thiophene-2-carboxamides as novel, potent and selective class II HDAC inhibitors. X-ray crystal structures of the HDAC 4 catalytic domain with a bound inhibitor demonstrate these compounds are active site inhibitors and bind in their hydrated form.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores de Histona Desacetilases , Tiofenos/síntese química , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Histona Desacetilases/classificação , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia , Zinco/química , Zinco/metabolismo
20.
J Med Chem ; 50(9): 2225-39, 2007 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-17428043

RESUMO

Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order to examine effects on HIV-integrase inhibitory potencies. One of the most interesting compounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide 38, with a CIC95 of 78 nM in the cell-based assay in the presence of serum proteins. The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys) and shows no liabilities in several counterscreening assays, highlighting its potential as a clinically useful antiviral agent.


Assuntos
Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Piridinas/síntese química , Pirimidinas/síntese química , Animais , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Linhagem Celular Tumoral , Cães , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/farmacologia , Meia-Vida , Humanos , Macaca mulatta , Ligação Proteica , Piridinas/química , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Replicação Viral
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