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1.
J Med Chem ; 64(13): 9100-9119, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34142835

RESUMO

In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Descoberta de Drogas , Inibidores da Fosfodiesterase 4/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptor Muscarínico M3/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Cobaias , Masculino , Estrutura Molecular , Inibidores da Fosfodiesterase 4/química , Doença Pulmonar Obstrutiva Crônica/metabolismo , Ratos , Ratos Endogâmicos BN , Ratos Sprague-Dawley , Receptor Muscarínico M3/metabolismo , Relação Estrutura-Atividade
2.
Genes Dev ; 35(13-14): 1005-1019, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34168039

RESUMO

N6-methyladenosine (m6A) is an abundant internal RNA modification, influencing transcript fate and function in uninfected and virus-infected cells. Installation of m6A by the nuclear RNA methyltransferase METTL3 occurs cotranscriptionally; however, the genomes of some cytoplasmic RNA viruses are also m6A-modified. How the cellular m6A modification machinery impacts coronavirus replication, which occurs exclusively in the cytoplasm, is unknown. Here we show that replication of SARS-CoV-2, the agent responsible for the COVID-19 pandemic, and a seasonal human ß-coronavirus HCoV-OC43, can be suppressed by depletion of METTL3 or cytoplasmic m6A reader proteins YTHDF1 and YTHDF3 and by a highly specific small molecule METTL3 inhibitor. Reduction of infectious titer correlates with decreased synthesis of viral RNAs and the essential nucleocapsid (N) protein. Sites of m6A modification on genomic and subgenomic RNAs of both viruses were mapped by methylated RNA immunoprecipitation sequencing (meRIP-seq). Levels of host factors involved in m6A installation, removal, and recognition were unchanged by HCoV-OC43 infection; however, nuclear localization of METTL3 and cytoplasmic m6A readers YTHDF1 and YTHDF2 increased. This establishes that coronavirus RNAs are m6A-modified and host m6A pathway components control ß-coronavirus replication. Moreover, it illustrates the therapeutic potential of targeting the m6A pathway to restrict coronavirus reproduction.


Assuntos
Coronavirus Humano OC43/fisiologia , Processamento Pós-Transcricional do RNA/genética , SARS-CoV-2/fisiologia , Replicação Viral/genética , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Linhagem Celular , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Metiltransferases/antagonistas & inibidores , Metiltransferases/metabolismo , Proteínas do Nucleocapsídeo , RNA Viral/metabolismo , Proteínas de Ligação a RNA/metabolismo , Replicação Viral/efeitos dos fármacos
3.
Nature ; 593(7860): 597-601, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33902106

RESUMO

N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5-7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy.

4.
J Med Chem ; 64(8): 5018-5036, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33783225

RESUMO

Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Piridonas/química , Pirimidinonas/química , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sítios de Ligação , Encéfalo/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Meia-Vida , Humanos , Doença de Huntington/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Morfolinos/química , Piridonas/metabolismo , Piridonas/uso terapêutico , Pirimidinonas/metabolismo , Pirimidinonas/uso terapêutico , Relação Estrutura-Atividade
5.
ACS Med Chem Lett ; 12(3): 380-388, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33738065

RESUMO

Using an iterative structure-activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC50, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington's disease.

6.
Bioorg Med Chem Lett ; 41: 127975, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33753262

RESUMO

The targeting of both the muscarinic and ß-adrenergic pathways is a well validated therapeutic approach for the treatment of chronic obstructive pulmonary disease (COPD). In this communication we report our effort to incorporate two pharmacologies into a single chemical entity, whose characteristic must be suitable for a once daily inhaled administration. Contextually, we aimed at a locally acting therapy with limited systemic absorption to minimize side effects. Our lung-tailored design of bifunctional compounds that combine the muscarinic and ß-adrenergic pharmacologies by the elaboration of the muscarinic inhibitor 7, successfully led to the potent, pharmacologically balanced muscarinic antagonist and ß2 agonist (MABA) 13.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncodilatadores/farmacologia , Descoberta de Drogas , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Broncodilatadores/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptor Muscarínico M3/antagonistas & inibidores , Receptor Muscarínico M3/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Relação Estrutura-Atividade
7.
J Med Chem ; 62(6): 2988-3008, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30840447

RESUMO

Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Doença de Huntington/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Modelos Animais de Doenças , Cães , Humanos , Células Madin Darby de Rim Canino , Camundongos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacocinética , Estudo de Prova de Conceito
8.
J Med Chem ; 62(4): 2140-2153, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30715878

RESUMO

Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirazóis/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Cães , Feminino , Humanos , Macaca fascicularis , Células Madin Darby de Rim Canino , Masculino , Camundongos SCID , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Pirazóis/síntese química , Pirazóis/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
9.
ACS Med Chem Lett ; 6(8): 925-9, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288695

RESUMO

Time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious undesirable drug-drug interactions and in rare cases drug-induced idiosyncratic toxicity. The reactive metabolites are often generated through multiple sequential biotransformations and form adducts with CYP enzymes to inactivate their function. The complexity of these processes makes addressing TDI liability very challenging. Strategies to mitigate TDI are therefore highly valuable in discovering safe therapies to benefit patients. In this Letter, we disclose our simplified approach toward addressing CYP3A TDI liabilities, guided by metabolic mechanism hypotheses. By adding a methyl group onto the α carbon of a basic amine, TDI activities of both the truncated and full molecules (7a and 11) were completely eliminated. We propose that truncated molecules, albeit with caveats, may be used as surrogates for full molecules to investigate TDI.

10.
ACS Med Chem Lett ; 1(7): 350-4, 2010 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-24900218

RESUMO

Amalgamation of the structure-activity relationship of two series of GlyT1 inhibitors developed at Merck led to the discovery of a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy of GlyT1 transporters in rhesus monkey as determined by displacement of a PET tracer ligand.

11.
Bioorg Med Chem Lett ; 19(8): 2235-9, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19318248

RESUMO

A series of heterocyclic sulfonamides have been developed which are potent and selective inhibitors of hGlyT1. SAR studies to optimise the in vitro and in vivo properties are described. Optimisation of the central scaffold resulted in cyclohexane sulfones 28 and 29, which have good PK properties and show promise for further development.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Sulfonamidas/administração & dosagem , Sulfonamidas/química , Administração Oral , Animais , Disponibilidade Biológica , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Humanos , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Sulfonamidas/metabolismo , Triazóis/administração & dosagem , Triazóis/síntese química
12.
J Med Chem ; 49(8): 2600-10, 2006 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-16610803

RESUMO

The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Agonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A , Piridazinas/farmacologia , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/síntese química , Sítios de Ligação , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/síntese química , Humanos , Ligantes , Estrutura Molecular , Piridazinas/administração & dosagem , Piridazinas/síntese química , Ratos , Proteínas Recombinantes/agonistas , Estereoisomerismo , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 16(5): 1175-9, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16406613

RESUMO

Imidazo[1,2-a]pyrimidines are GABA(A) receptor benzodiazepine binding site ligands which can exhibit functional selectivity for the alpha(3) subtype over the alpha(1) subtype. SAR studies to optimize this functional selectivity are described.


Assuntos
Imidazóis/química , Imidazóis/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Receptores de GABA-A/metabolismo , Ligantes , Estrutura Molecular , Pirimidinas/síntese química , Sensibilidade e Especificidade , Relação Estrutura-Atividade , Especificidade por Substrato
14.
J Med Chem ; 49(1): 35-8, 2006 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-16392789

RESUMO

A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Agonistas de Receptores de GABA-A , Pirimidinas/farmacologia , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Técnicas de Patch-Clamp , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Receptores de GABA-A , Relação Estrutura-Atividade
15.
Neuropharmacology ; 50(6): 677-89, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16430927

RESUMO

The cyclopyrrolone pagoclone binds with roughly equivalent high affinity (0.7-9.1nM) to the benzodiazepine binding site of human recombinant GABA(A) receptors containing either an alpha1, alpha2, alpha3 or alpha5 subunit. However, whereas it was a partial agonist at alpha1-, alpha2- and alpha5-containing GABA(A) receptors, pagoclone was a full agonist at receptors containing an alpha3 subunit. In the rat elevated plus maze assay pagoclone (3mg/kg) had significant anxiolytic-like activity but at all three doses tested (0.3, 1 and 3mg/kg p.o.) it produced a significant reduction in the total distance travelled. This sedative-like effect was confirmed in rat chain-pulling and spontaneous locomotor assays. Surprisingly, in the plasma and brain samples derived from the elevated plus maze assay, the major metabolite of pagoclone, 5'-hydroxy pagoclone, was present at 10-20-fold higher concentrations relative to the parent compound. In order to establish whether this metabolite might have pharmacological activity, we measured its affinity and efficacy profile and found that both were comparable to those of pagoclone with the exception that efficacy at the alpha1 subtype was considerably greater for 5'-hydroxy pagoclone compared with the parent. This metabolite had significant anxiolytic-like activity in the elevated plus maze but at these same doses (0.3-3mg/kg p.o.) also produced sedation. It is therefore likely that in rats 5'-hydroxy pagoclone mediates the majority of the pharmacological actions following pagoclone administration.


Assuntos
Comportamento Animal/efeitos dos fármacos , Naftiridinas/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Fibroblastos , Flumazenil/farmacologia , Moduladores GABAérgicos/farmacologia , Humanos , Indóis/farmacocinética , Isoindóis , Isomerismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Naftiridinas/sangue , Naftiridinas/química , Naftiridinas/farmacocinética , Subunidades Proteicas/metabolismo , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/química , Receptores de GABA-A/efeitos dos fármacos , Fatores de Tempo , Trítio/farmacocinética
16.
Bioorg Med Chem Lett ; 15(22): 4998-5002, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16153832

RESUMO

2,5-Dihydro-3H-pyrazolo[4,3-c]pyridin-3-ones are GABAA receptor benzodiazepine binding site ligands, which can exhibit functional selectivity for the alpha3 subtype over the alpha1 subtype. SAR studies to optimize this functional selectivity are described.


Assuntos
Compostos Azo/síntese química , Compostos Azo/metabolismo , Piridinas/química , Piridinas/metabolismo , Receptores de GABA-A/metabolismo , Compostos Azo/química , Ligantes , Estrutura Molecular , Piridinas/síntese química , Sensibilidade e Especificidade , Relação Estrutura-Atividade , Especificidade por Substrato
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