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1.
Commun Biol ; 4(1): 193, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33564093

RESUMO

SARS-CoV-2 Nsp15 is a uridine-specific endoribonuclease with C-terminal catalytic domain belonging to the EndoU family that is highly conserved in coronaviruses. As endoribonuclease activity seems to be responsible for the interference with the innate immune response, Nsp15 emerges as an attractive target for therapeutic intervention. Here we report the first structures with bound nucleotides and show how the enzyme specifically recognizes uridine moiety. In addition to a uridine site we present evidence for a second base binding site that can accommodate any base. The structure with a transition state analog, uridine vanadate, confirms interactions key to catalytic mechanisms. In the presence of manganese ions, the enzyme cleaves unpaired RNAs. This acquired knowledge was instrumental in identifying Tipiracil, an FDA approved drug that is used in the treatment of colorectal cancer, as a potential anti-COVID-19 drug. Using crystallography, biochemical, and whole-cell assays, we demonstrate that Tipiracil inhibits SARS-CoV-2 Nsp15 by interacting with the uridine binding pocket in the enzyme's active site. Our findings provide new insights for the development of uracil scaffold-based drugs.


Assuntos
Antivirais/farmacologia , /virologia , Endorribonucleases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirrolidinas/farmacologia , /enzimologia , Timina/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Células A549 , Antivirais/química , Antivirais/farmacocinética , Domínio Catalítico , Cristalografia por Raios X , Endorribonucleases/química , Endorribonucleases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Ligantes , Modelos Moleculares , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Timina/química , Timina/farmacocinética , Uridina/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
2.
SAR QSAR Environ Res ; 32(1): 51-70, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33401979

RESUMO

A Förster resonance energy transfer (FRET)-based assay was used to screen the FDA-approved compound library against the MERS-CoV helicase, an essential enzyme for virus replication within the host cell. Five compounds inhibited the helicase activity with submicromolar potencies (IC50, 0.73-1.65 µM) and ten compounds inhibited the enzyme with micromolar potencies (IC50, 19.6-502 µM). The molecular operating environment (MOE) was used to dock the identified inhibitors on the MERS-CoV helicase nucleotide binding. Strong inhibitors docked well in the nucleotide-binding site and established interactions with some of the essential residues. There was a reasonable correlation between the observed IC50 values and the MOE docking scores of the strong inhibitors (r 2 = 0.74), indicating the ability of the in silico docking model to predict the binding of strong inhibitors. In silico docking could be a useful complementary tool used with the FRET-based assay to predict new MERS-CoV helicase inhibitors. The identified inhibitors could potentially be used in the clinical development of new antiviral treatment for MERS-CoV and other coronavirus related diseases, including coronavirus disease 2019 (COVID-19).


Assuntos
Antivirais/química , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , DNA Helicases/efeitos dos fármacos , Inibidores Enzimáticos/farmacocinética , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Humanos , Relação Quantitativa Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
3.
Leukemia ; 34(11): 2903-2913, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32733012

RESUMO

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Terapia de Alvo Molecular , Mutação , Adulto , Idoso , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Medula Óssea/patologia , Análise Mutacional de DNA , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
4.
Am J Physiol Renal Physiol ; 319(1): F84-F92, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475130

RESUMO

Loss of muscle proteins increases the morbidity and mortality of patients with chronic kidney disease (CKD), and there are no reliable preventive treatments. We uncovered a STAT3/CCAAT-enhancer-binding protein-δ to myostatin signaling pathway that activates muscle protein degradation in mice with CKD or cancer; we also identified a small-molecule inhibitor of STAT3 (TTI-101) that blocks this pathway. To evaluate TTI-101 as a treatment for CKD-induced cachexia, we measured TTI-101 pharmacokinetics and pharmacodynamics in control and CKD rats that were orally administered TTI-101or its diluent. The following two groups of gavage-fed rats were studied: sham-operated control rats and CKD rats. Plasma was collected serially (0, 0.25, 0.5, 1, 2, 4, 8, and 24 h) following TTI-101 administration (at oral doses of 0, 10, 30, or 100 mg/kg). Plasma levels of TTI-101 were measured by LC-MS/MS, and pharmacokinetic results were analyzed with the PKSolver program. Plasma TTI-101 levels increased linearly with doses; the maximum plasma concentrations and time to maximal plasma levels (~1 h) were similar in sham-operated control rats and CKD rats. Notably, gavage treatment of TTI-101 for 3 days produced TTI-101 muscle levels in sham control rats and CKD rats that were not significantly different. CKD rats that received TTI-101 for 7 days had suppression of activated STAT3 and improved muscle grip strength; there also was a trend for increasing body and muscle weights. TTI-101 was tolerated at doses of 100 mg·kg-1·day-1 for 7 days. These results with TTI-101 in rats warrant its development as a treatment for cachexia in humans.


Assuntos
Inibidores Enzimáticos/farmacologia , Músculo Esquelético/efeitos dos fármacos , Naftóis/farmacologia , Proteólise/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Força da Mão , Músculo Esquelético/metabolismo , Naftóis/farmacocinética , Ratos , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem
5.
PLoS One ; 15(5): e0233468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469975

RESUMO

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Transtornos da Memória/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Oxidiazóis/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/psicologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Epigênese Genética/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacocinética , Oxidiazóis/química , Oxidiazóis/farmacocinética , Ratos , Ratos Sprague-Dawley
6.
Nat Chem Biol ; 16(6): 667-675, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32393901

RESUMO

N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as a CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor. LEI-401 reduced NAE levels in neuroblastoma cells and in the brain of freely moving mice, but not in NAPE-PLD KO cells and mice, respectively. LEI-401 activated the hypothalamus-pituitary-adrenal axis and impaired fear extinction, thereby emulating the effect of a cannabinoid CB1 receptor antagonist, which could be reversed by a fatty acid amide hydrolase inhibitor. Our findings highlight the distinctive role of NAPE-PLD in NAE biosynthesis in the brain and suggest the presence of an endogenous NAE tone controlling emotional behavior.


Assuntos
Comportamento Animal/efeitos dos fármacos , Inibidores Enzimáticos/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Fosfatidiletanolaminas/metabolismo , Fosfolipase D/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Proteínas Sanguíneas/metabolismo , Encéfalo/metabolismo , Antagonistas de Receptores de Canabinoides/metabolismo , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Medo/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Receptores de Canabinoides/metabolismo , Transdução de Sinais
7.
Cancer Chemother Pharmacol ; 85(5): 995-1001, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32318809

RESUMO

PURPOSE: Fedratinib, an oral, selective Janus kinase 2 inhibitor with activity against both wild-type and mutant Janus kinase 2, has pH-dependent solubility, with free solubility at pH 1. Concomitant administration of drugs that reduce gastric acid secretion, such as pantoprazole, may decrease the absorption of fedratinib and affect patient outcomes. The aim of this study was to evaluate the impact of 7-day repeated 40-mg doses of pantoprazole on the pharmacokinetic (PK) properties of a single 500-mg dose of fedratinib in healthy male subjects. METHODS: In this phase I, single-center, open-label, two-period, two-treatment, fixed-sequence crossover study, healthy male subjects were administered a single dose of fedratinib 500 mg on day 1 in Period 1, followed by pantoprazole 40 mg daily for 7 days (day 1 to day 7) and a single dose of fedratinib 500 mg on day 7 in Period 2. After the discontinuation of nine subjects due to vomiting, the protocol was amended to provide ondansetron as antiemetic prophylaxis to an additional ten enrolled subjects. RESULTS: Twenty-six subjects were included. Repeated doses of pantoprazole 40 mg resulted in clinically insignificant increases in fedratinib exposure. Maximum plasma concentration increased by 1.09-fold and area under the plasma concentration-time curve from time 0 to infinity increased by 1.15-fold. All treatment-emergent adverse events were mild or moderate, except for one instance of neutropenia, which was considered unrelated to study intervention. CONCLUSION: Coadministration with pantoprazole did not have clinically meaningful effects on fedratinib PK. No new or unexpected safety signals were observed with fedratinib.


Assuntos
Interações Medicamentosas , Janus Quinase 2/antagonistas & inibidores , Pantoprazol , Pirrolidinas , Sulfonamidas , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Voluntários Saudáveis , Humanos , Masculino , Pantoprazol/administração & dosagem , Pantoprazol/efeitos adversos , Pantoprazol/farmacocinética , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Resultado do Tratamento
8.
J Med Chem ; 63(9): 4929-4956, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32248693

RESUMO

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.


Assuntos
Antimaláricos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Pirróis/uso terapêutico , Animais , Antimaláricos/síntese química , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Camundongos SCID , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/enzimologia , Ligação Proteica , Pirróis/síntese química , Pirróis/metabolismo , Pirróis/farmacocinética , Ratos , Relação Estrutura-Atividade
9.
J Med Chem ; 63(9): 4528-4554, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302123

RESUMO

Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a meta-relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue.


Assuntos
Aminoquinolinas/farmacologia , Ácido Aspártico/química , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Aminoquinolinas/síntese química , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacocinética , Animais , Barreira Hematoencefálica/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Mutagênese Sítio-Dirigida , Mutação , Óxido Nítrico Sintase Tipo I/química , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Permeabilidade , Ligação Proteica , Ratos , Relação Estrutura-Atividade
10.
J Pharmacol Exp Ther ; 374(1): 223-232, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32238455

RESUMO

1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) and 1-(4-trifluoro-methoxy-phenyl)-3-(1-cyclopropanecarbonyl-piperidin-4-yl)-urea (TCPU) are potent inhibitors of soluble epoxide hydrolase (sEH) that have much better efficacy in relieving nociceptive response than the Food and Drug Administration-approved drug gabapentin in a rodent model of diabetic neuropathy. Experiments conducted in sEH knockout mice or with coadministration of a potent sEH displacer demonstrated that the pharmacokinetics of TPPU and TCPU were influenced by the specific binding to their pharmacologic target sEH, a phenomenon known as target-mediated drug disposition (TMDD). To quantitatively characterize the complex pharmacokinetics of TPPU and TCPU and gain better understanding on their target occupancy, population pharmacokinetics analysis using a nonlinear mixed-effect modeling approach was performed in the current study. The final model was a novel simultaneous TMDD interaction model, in which TPPU and TCPU compete for sEH, with TCPU binding to an additional unknown target pool with larger capacity that we refer to as a refractory pool. The total amount of sEH enzyme in mice was predicted to be 16.2 nmol, which is consistent with the experimental value of 10 nmol. The dissociate rate constants of TPPU and TCPU were predicted to be 2.24 and 2.67 hours-1, respectively, which is close to the values obtained from in vitro experiments. Our simulation result predicted that 90% of the sEH will be occupied shortly after a low dose of 0.3 mg/kg TPPU administration, with ≥40% of sEH remaining to be bound with TPPU for at least 7 days. Further efficacy experiments are warranted to confirm the predicted target occupancy. SIGNIFICANCE STATEMENT: Although target-mediated drug disposition (TMDD) models have been well documented, most of them were established in a single compound scenario. Our novel model represents the first TMDD interaction model for two small-molecule compounds competing for the same pharmacological target.


Assuntos
Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Modelos Biológicos , Terapia de Alvo Molecular , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Inibidores Enzimáticos/farmacocinética , Epóxido Hidrolases/química , Compostos de Fenilureia/farmacocinética , Piperidinas/farmacocinética , Solubilidade
11.
Nat Chem Biol ; 16(5): 497-506, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32231343

RESUMO

We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance by multiple types of treatment results in a stable cell state marked by high levels of polyunsaturated lipids and an acquired dependency on GPX4. Unfortunately, all existing inhibitors of GPX4 act covalently via a reactive alkyl chloride moiety that confers poor selectivity and pharmacokinetic properties. Here, we report our discovery that masked nitrile-oxide electrophiles, which have not been explored previously as covalent cellular probes, undergo remarkable chemical transformations in cells and provide an effective strategy for selective targeting of GPX4. The new GPX4-inhibiting compounds we describe exhibit unexpected proteome-wide selectivity and, in some instances, vastly improved physiochemical and pharmacokinetic properties compared to existing chloroacetamide-based GPX4 inhibitors. These features make them superior tool compounds for biological interrogation of ferroptosis and constitute starting points for development of improved inhibitors of GPX4.


Assuntos
Inibidores Enzimáticos/farmacologia , Nitrilos/química , Nitrilos/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Ferroptose/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos SCID , Sondas Moleculares/química , Terapia de Alvo Molecular , Óxidos/química , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/química , Pró-Fármacos/química , Ratos Wistar , Selenocisteína/química , Selenocisteína/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
12.
J Med Chem ; 63(13): 6679-6693, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32250617

RESUMO

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Modelos Moleculares , Mutação , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Ensaios Antitumorais Modelo de Xenoenxerto
13.
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
14.
Food Chem ; 318: 126482, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32145543

RESUMO

We have examined the trans-resveratrol/lipase interaction by quantitative and qualitative analyses of fluorescence spectra, molecular docking and quantum-chemical calculations at DFT level. Interactions of CpLIP2 from C. parapsilosis CBS 604 and trans-resveratrol were confirmed with a major contribution of tryptophan residues to fluorescence quenching. A thermodynamic study across a wide temperature range was consistent with the presence of a single binding site with a binding free energy of -24 kJ/mol. Nevertheless, trans-resveratrol competitively inhibited CpLIP2 activity. Molecular docking and quantum-chemical calculations were consistent with a strong binding of trans-resveratrol to the CpLIP2 catalytic site via electrostatic and hydrophobic forces. The structural analysis quantitatively revealed an energy transfer from W51 and W350 to trans-resveratrol with a distance of 32 Å. Precise understanding of trans-resveratrol/CpLIP2 interactions has important implications on lipases for screening of stilbenoid.


Assuntos
Candida parapsilosis/enzimologia , Lipase/metabolismo , Resveratrol/metabolismo , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Fluorescência , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Lipase/antagonistas & inibidores , Lipase/química , Simulação de Acoplamento Molecular , Resveratrol/química , Resveratrol/farmacocinética , Termodinâmica
15.
AAPS PharmSciTech ; 21(3): 98, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32128656

RESUMO

Oseltamivir is a neuraminidase inhibitor widely used to treat and prevent influenza A and B infections, although its safety and pharmacokinetics have not been evaluated in patients with severe hepatic impairment. A physiologically based pharmacokinetic (PBPK) model of the prodrug oseltamivir and its active metabolite, oseltamivir carboxylate (OC), was established and validated to simulate their disposition in adults and predict the exposure in patients with Child-Pugh C cirrhosis (CP-C). The simulated results from PBPK modeling and the observed data after oral administration of various oseltamivir regimens were consistent according to the fold error values of less than 2. Furthermore, the clinical observations published in the literature were comparable with our pharmacokinetic predictions. In patients with CP-C, the oseltamivir Cmax was approximately 2-fold increased, and its AUC was approximately 6-fold higher compared with those in normal subjects. In contrast, the AUC of OC in CP-C patients did not differ significantly from that in normal subjects, whereas its Cmax was reduced by approximately 30% in the patients. Examination of drug exposure in different health conditions indicated that the oseltamivir exposure was significantly increased in conditions with elevated cirrhosis severity, which might be associated with a higher risk of adverse drug effects, e.g., neuropsychiatric adverse events (NPAEs). In conclusion, the pharmacokinetics of oseltamivir and OC were correctly predicted by PBPK modeling. The model further predicted that the pharmacokinetics of oseltamivir might be altered in liver cirrhosis, depending on the degree of severity.


Assuntos
Antivirais/farmacocinética , Simulação por Computador , Cirrose Hepática/metabolismo , Modelos Biológicos , Oseltamivir/análogos & derivados , Oseltamivir/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Cirrose Hepática/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Oseltamivir/administração & dosagem , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Adulto Jovem
16.
Nat Rev Rheumatol ; 16(3): 167-178, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32055040

RESUMO

The introduction of biologic DMARDs into rheumatology has resulted in a substantial reduction of the burden of many rheumatic diseases. In the slipstream of the success achieved with these biologic DMARDs, some conventional immunosuppressive drugs have also found use in new indications. Notably, mycophenolate mofetil, azathioprine and tacrolimus have made their way from solid organ transplantation drugs to become useful assets in rheumatology practice. Mycophenolate mofetil and azathioprine inhibit the purine pathway and subsequently diminish cell proliferation. Both drugs have a pivotal role in the treatment of various rheumatic diseases, including lupus nephritis. Tacrolimus inhibits lymphocyte activation by inhibiting the calcineurin pathway. Mycophenolate mofetil and tacrolimus are, among other indications, increasingly being recognized as useful drugs in the treatment of interstitial lung disease in systemic rheumatic diseases and skin fibrosis in systemic sclerosis. A broad array of trials with mycophenolate mofetil, azathioprine and/or tacrolimus are ongoing within the field of rheumatology that might provide further novel avenues for the use of these drugs. In this Review, we discuss the historical perspective, pharmacodynamics, clinical indications and novel avenues for mycophenolate mofetil, azathioprine and tacrolimus in rheumatology.


Assuntos
Azatioprina/uso terapêutico , Ácido Micofenólico/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Reumatologia , Tacrolimo/uso terapêutico , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Azatioprina/farmacocinética , Quimioterapia Combinada , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Ácido Micofenólico/farmacocinética , Tacrolimo/farmacocinética
17.
J Med Chem ; 63(7): 3552-3562, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32073266

RESUMO

We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.


Assuntos
DNA/química , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Pró-Fármacos/farmacologia , Compostos de Espiro/farmacologia , Animais , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Eutérios , Masculino , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Relação Estrutura-Atividade
18.
J Med Chem ; 63(4): 1660-1670, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31990537

RESUMO

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.


Assuntos
HDL-Colesterol/metabolismo , Inibidores Enzimáticos/farmacologia , Cetonas/farmacologia , Lipase/antagonistas & inibidores , Oxidiazóis/farmacologia , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Cetonas/síntese química , Cetonas/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Relação Estrutura-Atividade
19.
J Med Chem ; 63(4): 1684-1698, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31990540

RESUMO

Vacuolar type ATPase (V-ATPase) has recently emerged as a promising novel anticancer target based on extensive in vitro and in vivo studies with archazolids, complex polyketide macrolides, which present the most potent V-ATPase inhibitors known to date. Herein, we report a biomimetic, one-step preparation of archazolid F, the most potent and least abundant archazolid, the design and synthesis of five novel, carefully selected archazolid analogues, and the biological evaluation of these antiproliferative agents, leading to the discovery of a very potent but profoundly simplified archazolid analogue. Furthermore, the first general biological profiling of the archazolids against a broad range of more than 100 therapeutically relevant targets is reported, leading to the discovery of novel and important targets. Finally, first pharmacokinetic data of these natural products are disclosed. All of these data are relevant in the further preclinical development of the archazolids as well as the evaluation of V-ATPases as a novel and powerful class of anticancer targets.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Macrolídeos/farmacologia , Tiazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Macrolídeos/síntese química , Macrolídeos/farmacocinética , Camundongos , Ratos , Tiazóis/síntese química , Tiazóis/farmacocinética , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores
20.
J Med Chem ; 63(3): 1337-1360, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31910017

RESUMO

p300 and CREB-binding protein (CBP) are ubiquitously expressed pleiotropic lysine acetyltransferases and play a key role as transcriptional co-activators that are essential for a multitude of cellular processes. Despite great importance, there is a lack of highly selective, potent, druglike p300/CBP inhibitors. Through the artificial-intelligence-assisted drug discovery pipeline and further optimization, we reported the discovery of novel, highly selective, potent small-molecule inhibitors of p300/CBP histone acetyltransferases (HAT) with desired druglike properties, exemplified by B026. Our data demonstrated that B026, with half maximal inhibitory concentration (IC50) values of 1.8 nM to p300 and 9.5 nM to CBP enzyme inhibitory activity, is the most potent, selective p300/CBP HAT inhibitor. Moreover, B026 achieves significant and dose-dependent tumor growth inhibition in an animal model of human cancer, suggesting that B026 is a highly promising p300/CBP HAT inhibitor and warrants extensive preclinical investigation as a potential clinical development candidate.


Assuntos
Antineoplásicos/uso terapêutico , Proteína de Ligação a CREB/antagonistas & inibidores , Proteína p300 Associada a E1A/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos de Espiro/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Conjuntos de Dados como Assunto , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Redes Neurais de Computação , Ratos Sprague-Dawley , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Relação Estrutura-Atividade
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