RESUMO
As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.
Assuntos
COVID-19 , Glutamina , Humanos , Glutamina/química , SARS-CoV-2 , Cisteína Endopeptidases/química , Invenções , Inibidores de Proteases/farmacologia , Amidas , Antivirais/farmacologia , Antivirais/químicaRESUMO
PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.
Assuntos
Inibidores de Fosfodiesterase , Esquizofrenia , Humanos , Cristalografia por Raios X , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/química , Esquizofrenia/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that can lead to eradication of persistent viral reservoirs in people living with HIV-1 (PLWH) remains an outstanding challenge to achieving cure. Utilizing a phenotypic screen, we identified a novel chemical class capable of killing HIV-1 infected peripheral blood mononuclear cells. Tool compounds ICeD-1 and ICeD-2 ("inducer of cell death-1 and 2"), optimized for potency and selectivity from screening hits, were used to deconvolute the mechanism of action using a combination of chemoproteomic, biochemical, pharmacological, and genetic approaches. We determined that these compounds function by modulating dipeptidyl peptidase 9 (DPP9) and activating the caspase recruitment domain family member 8 (CARD8) inflammasome. Efficacy of ICeD-1 and ICeD-2 was dependent on HIV-1 protease activity and synergistic with efavirenz, which promotes premature activation of HIV-1 protease at high concentrations in infected cells. This in vitro synergy lowers the efficacious cell kill concentration of efavirenz to a clinically relevant dose at concentrations of ICeD-1 or ICeD-2 that do not result in complete DPP9 inhibition. These results suggest engagement of the pyroptotic pathway as a potential approach to eliminate HIV-1 infected cells.
Assuntos
Infecções por HIV , HIV-1 , Alcinos , Benzoxazinas , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Ciclopropanos , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Infecções por HIV/tratamento farmacológico , HIV-1/metabolismo , Humanos , Inflamassomos/metabolismo , Leucócitos Mononucleares , Proteínas de Neoplasias/metabolismoRESUMO
We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Kiâ¯=â¯22.4⯵M), exhibited good binding efficiencies (LBEâ¯=â¯0.49, LLEâ¯=â¯4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Fosfodiesterase/química , Animais , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Meia-Vida , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/farmacocinética , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
High-throughput screening (HTS) has enabled millions of compounds to be assessed for biological activity, but challenges remain in the prioritization of hit series. While biological, absorption, distribution, metabolism, excretion, and toxicity (ADMET), purity, and structural data are routinely used to select chemical matter for further follow-up, the scarcity of historical ADMET data for screening hits limits our understanding of early hit compounds. Herein, we describe a process that utilizes a battery of in-house quantitative structure-activity relationship (QSAR) models to generate in silico ADMET profiles for hit series to enable more complete characterizations of HTS chemical matter. These profiles allow teams to quickly assess hit series for desirable ADMET properties or suspected liabilities that may require significant optimization. Accordingly, these in silico data can direct ADMET experimentation and profoundly impact the progression of hit series. Several prospective examples are presented to substantiate the value of this approach.
Assuntos
Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Preparações Farmacêuticas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Simulação por Computador , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Preparações Farmacêuticas/metabolismo , Farmacocinética , Farmacologia , Relação Quantitativa Estrutura-AtividadeRESUMO
A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.
RESUMO
Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer.
Assuntos
Descoberta de Drogas , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Esquizofrenia/tratamento farmacológico , Animais , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Ratos , Ratos Wistar , Esquizofrenia/enzimologia , Relação Estrutura-AtividadeRESUMO
Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.
Assuntos
Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-Atividade , Animais , Técnicas de Química Sintética , Cristalografia por Raios X , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Masculino , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/química , Ratos Wistar , Esquizofrenia/tratamento farmacológicoRESUMO
An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M(1) positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified.
Assuntos
Ácidos Carboxílicos/síntese química , Quinolinas/química , Receptor Muscarínico M1/metabolismo , Regulação Alostérica , Animais , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Humanos , Ligação Proteica , Ratos , Bibliotecas de Moléculas PequenasRESUMO
The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 microM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/química , Sistema Cardiovascular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Piperidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
The novel T-type antagonist ( S)- 5 has been prepared and evaluated in in vitro and in vivo assays for T-type calcium ion channel activity. Structural modification of the piperidine leads 1 and 2 afforded the fluorinated piperidine ( S)- 5, a potent and selective antagonist that displayed in vivo CNS efficacy without adverse cardiovascular effects.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Desenho de Fármacos , Piperidinas/síntese química , Piperidinas/farmacologia , Piranos/síntese química , Piranos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/química , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Frequência Cardíaca/efeitos dos fármacos , Modelos Animais , Estrutura Molecular , Piperidinas/química , Piranos/química , Ratos , Relação Estrutura-AtividadeRESUMO
The evolution of a convergent strategy that led to efficient, enantioselective syntheses of both natural (+)- and unnatural (-)-guanacastepene E and formal total syntheses of (+)- and (-)-guanacastepene A is described. A union of five- and six-membered ring intermediates by an efficient pi-allyl Stille cross-coupling reaction was followed by an intramolecular enone-olefin [2 + 2] photocycloaddition and a stereoelectronically controlled, reductive fragmentation of the resulting cyclobutyl ketone. The latter two transformations enabled controlled formation of the C-11 quaternary stereocenter and the central seven-membered ring of the guanacastepenes. An enantiospecific synthesis of the functionalized five-membered ring vinyl stannane from the monoterpene R-(-)-carvone featuring a carbon-carbon bond forming ring contraction was also developed.
Assuntos
Química Orgânica/métodos , Ciclobutanos/química , Diterpenos/síntese química , Reagentes de Ligações Cruzadas/química , Diterpenos/química , EstereoisomerismoRESUMO
This article describes recent progress towards validation of the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia in preclinical models. Schizophrenia, a complex disease characterized by positive, negative and cognitive symptoms, affects 1% of the world population and requires lifelong, daily maintenance therapy. For the last several decades, thinking in this field has been dominated by the hypothesis that hyperfunction of dopamine pathways played a key role in schizophrenia. However, the therapeutic agents developed from this hypothesis have a slow onset of action and tend to improve only the positive symptoms of the disease. The NMDA receptor antagonist PCP has been shown to induce the positive, negative and cognitive symptoms of schizophrenia in healthy patients and cause a resurgence of symptoms in stable patients. These observations led to the NMDA receptor hypofunction hypothesis as an alternative theory for the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents has the potential to ameliorate the symptoms of schizophrenia. To date, NMDA receptor currents can be modulated by either direct action on modulatory sites on the NMDA receptor (i.e., the glycine co-agonist binding site) or indirectly by activation of G-protein coupled receptors (GPCRs) known to potentiate NMDA receptor function (i.e., mGluR5). This review will discuss the NMDA receptor hypofunction hypothesis, the NMDA receptor as an emerging target for the development of novel antipsychotic agents and progress towards in vivo target validation with GlyT1 inhibitors and mGluR5 positive allosteric modulators. Other potential targets for modulating NMDA receptor currents (polyamine sites, muscarinic receptors, etc...) will also be addressed briefly.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Antipsicóticos/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de N-Metil-D-Aspartato/fisiologia , Esquizofrenia/fisiopatologia , Animais , Benzamidas/farmacologia , Benzimidazóis/farmacologia , Encéfalo/metabolismo , Glicina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Humanos , Ftalimidas/farmacologia , Pirazóis/farmacologia , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Sarcosina/análogos & derivados , Sarcosina/farmacologia , Esquizofrenia/etiologia , Esquizofrenia/prevenção & controle , Transmissão Sináptica/efeitos dos fármacosRESUMO
This review presents a summary of reactions performed using microwave irradiation on a multigram scale. Results are described in the context of existing equipment, and equipment currently in development, for the processing of multigram to kilogram quantities of materials including single- and multimode microwave reactors and batch, batch-flow and continuous-flow systems. Although limited in number, reports found in the literature to date suggest that with appropriate controls, reproducible scale-up of microwave reactions is feasible and requires minimal re-optimization of laboratory-scale reaction conditions. This feature, along with the dramatic reductions in reaction time generally observed for microwave reactions suggests that application of this technology in process research could be beneficial.
Assuntos
Micro-Ondas , Compostos Orgânicos/síntese química , Benzopiranos/síntese química , Técnicas de Química Combinatória , Dioxolanos/síntese química , Quinazolinas/síntese química , Temperatura , Tiocarbamatos/síntese química , Fatores de TempoRESUMO
Positive allosteric modulators of metabotropic glutamate receptors (mGluRs) are the subject of intensive research due to their emerging therapeutic potential for a range of psychiatric and neurological disorders such as pain, anxiety, cognition, Parkinson's disease and schizophrenia. Positive allosteric modulators, which are small molecules capable of enhancing agonist-mediated receptor activity while possessing no intrinsic agonist activity, have recently been described for group I (mGluR1 and mGluR5), group II (mGluR2) and group III (mGluR4) mGluRs. Relative to classical mGluR agonists, these molecules offer improved selectivity versus other mGluRs and chemical tractability, and may reduce the liability of receptor desensitization.
Assuntos
Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Animais , Humanos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/químicaRESUMO
Microwave-assisted organic synthesis (MAOS) addresses the need for accelerated chemical synthesis by providing many advantages over classical thermal conditions. Microwave instruments produced by Biotage, CEM and Milestone enable chemistry to be safely and reproducibly performed on various scales and in a parallel fashion. To illustrate the high utility of this technology for lead development, our Akt kinase program will be described wherein MAOS played a pivotal role in the identification of isozyme-selective Akt inhibitors.:
RESUMO
[reaction: see text] This Letter describes a concise, diastereoselective synthesis of the tricyclic carbon framework of the guanacastepene family of natural products. An intermolecular Diels-Alder reaction established a remote stereochemical relationship and facilitated a synthesis of allylic acetate 3, which was subsequently joined with vinylstananne 9 via a Stille coupling. An intramolecular [2 + 2] photocycloaddition then afforded complex cyclobutyl ketone 19, which underwent a stereoelectronically controlled fragmentation to the guanacastepene architecture on treatment with samarium diiodide.