RESUMEN
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.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Fosfodiesterasa/química , Animales , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Semivida , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Conformación Molecular , Simulación de Dinámica Molecular , Inhibidores de Fosfodiesterasa/metabolismo , Inhibidores de Fosfodiesterasa/farmacocinética , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacocinética , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Descubrimiento de Drogas , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Esquizofrenia/tratamiento farmacológico , Animales , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Macaca mulatta , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Ratas , Ratas Wistar , Esquizofrenia/enzimología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
COVID-19 , Glutamina , Humanos , Glutamina/química , SARS-CoV-2 , Cisteína Endopeptidasas/química , Invenciones , Inhibidores de Proteasas/farmacología , Amidas , Antivirales/farmacología , Antivirales/químicaRESUMEN
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.
Asunto(s)
Inhibidores de Fosfodiesterasa , Esquizofrenia , Humanos , Cristalografía por Rayos X , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Pirimidinas/química , Esquizofrenia/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Infecciones por VIH , VIH-1 , Alquinos , Benzoxazinas , Proteínas Adaptadoras de Señalización CARD/metabolismo , Ciclopropanos , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Infecciones por VIH/tratamiento farmacológico , VIH-1/metabolismo , Humanos , Inflamasomas/metabolismo , Leucocitos Mononucleares , Proteínas de Neoplasias/metabolismoRESUMEN
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.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Quinolinas/química , Receptor Muscarínico M1/metabolismo , Regulación Alostérica , Animales , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Humanos , Unión Proteica , Ratas , Bibliotecas de Moléculas PequeñasRESUMEN
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.
Asunto(s)
Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Preparaciones Farmacéuticas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Simulación por Computador , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Farmacología , Relación Estructura-Actividad CuantitativaRESUMEN
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.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Antipsicóticos/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Receptores de N-Metil-D-Aspartato/fisiología , Esquizofrenia/fisiopatología , Animales , Benzamidas/farmacología , Bencimidazoles/farmacología , Encéfalo/metabolismo , Glicina/antagonistas & inhibidores , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Humanos , Ftalimidas/farmacología , Pirazoles/farmacología , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Sarcosina/análogos & derivados , Sarcosina/farmacología , Esquizofrenia/etiología , Esquizofrenia/prevención & control , Transmisión Sináptica/efectos de los fármacosRESUMEN
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.
RESUMEN
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.
Asunto(s)
Receptores de Glutamato Metabotrópico/efectos de los fármacos , Animales , Humanos , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/químicaRESUMEN
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.
Asunto(s)
Microondas , Compuestos Orgánicos/síntesis química , Benzopiranos/síntesis química , Técnicas Químicas Combinatorias , Dioxolanos/síntesis química , Quinazolinas/síntesis química , Temperatura , Tiocarbamatos/síntesis química , Factores de TiempoRESUMEN
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.:
RESUMEN
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.
Asunto(s)
Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Relación Estructura-Actividad , Animales , Técnicas de Química Sintética , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Humanos , Masculino , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/química , Hidrolasas Diéster Fosfóricas/metabolismo , Pirimidinas/química , Ratas Wistar , Esquizofrenia/tratamiento farmacológicoRESUMEN
[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.
Asunto(s)
Diterpenos/síntesis química , Diterpenos/química , Estructura MolecularRESUMEN
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.
Asunto(s)
Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Diseño de Fármacos , Piperidinas/síntesis química , Piperidinas/farmacología , Piranos/síntesis química , Piranos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/química , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Frecuencia Cardíaca/efectos de los fármacos , Modelos Animales , Estructura Molecular , Piperidinas/química , Piranos/química , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacología , Animales , Bloqueadores de los Canales de Calcio/química , Sistema Cardiovascular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Piperidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
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.