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1.
J Chem Inf Model ; 60(9): 4144-4152, 2020 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-32309939

RESUMEN

Two orthogonal approaches for hit identification in drug discovery are large-scale in vitro and in silico screening. In recent years, due to the emergence of new targets and a rapid increase in the size of the readily synthesizable chemical space, there is a growing emphasis on the integration of the two techniques to improve the hit finding efficiency. Here, we highlight three examples of drug discovery projects at Merck & Co., Inc., Kenilworth, NJ, USA in which different virtual screening (VS) techniques, each specifically tailored to leverage knowledge available for the target, were utilized to augment the selection of high-quality chemical matter for in vitro assays and to enhance the diversity and tractability of hits. Central to success is a fully integrated workflow combining in silico and experimental expertise at every stage of the hit identification process. We advocate that workflows encompassing VS as part of an integrated hit finding plan should be widely adopted to accelerate hit identification and foster cross-functional collaborations in modern drug discovery.


Asunto(s)
Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Simulación por Computador , Bibliotecas de Moléculas Pequeñas
2.
Bioorg Med Chem Lett ; 27(1): 109-113, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-27894874

RESUMEN

Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer's disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro-in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinonas/farmacología , Pirroles/farmacología , Enfermedad de Alzheimer/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinonas/química , Pirimidinonas/metabolismo , Pirroles/química , Pirroles/metabolismo , Ratas , Relación Estructura-Actividad
3.
Bioorg Med Chem Lett ; 27(1): 114-120, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-27816515

RESUMEN

The initial structure activity relationships around an isoindoline uHTS hit will be described. Information gleaned from ligand co-crystal structures allowed for rapid refinements in both MARK potency and kinase selectivity. These efforts allowed for the identification of a compound with properties suitable for use as an in vitro tool compound for validation studies on MARK as a viable target for Alzheimer's disease.


Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinonas/farmacología , Pirroles/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Línea Celular , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad
4.
Bioorg Med Chem Lett ; 24(8): 1968-73, 2014 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-24666646

RESUMEN

A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition.


Asunto(s)
Aminoimidazol Carboxamida/síntesis química , Aminoimidazol Carboxamida/farmacología , Janus Quinasa 2/antagonistas & inhibidores , Tiofenos/síntesis química , Tiofenos/farmacología , Aminoimidazol Carboxamida/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Microsomas/efectos de los fármacos , Microsomas/enzimología , Modelos Biológicos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Tiofenos/química
5.
J Med Chem ; 65(5): 3776-3785, 2022 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-35192762

RESUMEN

Increasing the efficiency of the drug discovery process is a challenge faced by drug hunters everywhere. One strategy medicinal chemists employ to meet this challenge is learning from knowledge sources within and beyond their organization. In this Perspective, we discuss the evolution of mechanisms for medicinal chemistry knowledge capture and sharing at Merck & Co. over the past 15 years. We describe our approach to knowledge management and report on the multiple enduring and complementary teams and initiatives we have created to capture and share knowledge within a geographically diverse medicinal chemistry community. In addition, this Perspective will share the benefits we have observed and also reflect on what has allowed our efforts to be both successful and sustainable.


Asunto(s)
Química Farmacéutica , Descubrimiento de Drogas
6.
J Med Chem ; 65(7): 5675-5689, 2022 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-35332774

RESUMEN

Stereochemically and structurally complex cyclic dinucleotide-based stimulator of interferon genes (STING) agonists were designed and synthesized to access a previously unexplored chemical space. The assessment of biochemical affinity and cellular potency, along with computational, structural, and biophysical characterization, was applied to influence the design and optimization of novel STING agonists, resulting in the discovery of MK-1454 as a molecule with appropriate properties for clinical development. When administered intratumorally to immune-competent mice-bearing syngeneic tumors, MK-1454 exhibited robust tumor cytokine upregulation and effective antitumor activity. Tumor shrinkage in mouse models that are intrinsically resistant to single-agent therapy was further enhanced when treating the animals with MK-1454 in combination with a fully murinized antimouse PD-1 antibody, mDX400. These data support the development of STING agonists in combination with pembrolizumab (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 therapy.


Asunto(s)
Proteínas de la Membrana , Neoplasias , Animales , Citocinas , Humanos , Inmunoterapia/métodos , Interferones , Ratones , Neoplasias/tratamiento farmacológico
7.
Oncoimmunology ; 10(1): 1896643, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33796403

RESUMEN

Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE2-mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4 receptor. EP4 inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8+ T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitro experiments demonstrated that MF-766 restored PGE2-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in THP-1 cells and human blood, and PGE2-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ in CD8+ T-cells by PGE2 and impaired suppression of CD8+ T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE2. In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE2 high TME. Our studies demonstrate that the combination of EP4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.


Asunto(s)
Linfocitos T CD8-positivos , Subtipo EP4 de Receptores de Prostaglandina E , Animales , Ciclooxigenasa 2 , Dinoprostona , Macrófagos , Ratones
8.
Science ; 369(6506)2020 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-32820094

RESUMEN

Pharmacological activation of the STING (stimulator of interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-ß secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti-PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de la Membrana/metabolismo , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Humanos
9.
J Med Chem ; 60(16): 6771-6780, 2017 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-28418656

RESUMEN

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 Cuantitativa
10.
ACS Med Chem Lett ; 7(12): 1151-1155, 2016 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-27994755

RESUMEN

Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a Salmonella strain.

11.
J Med Chem ; 58(4): 1929-39, 2015 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-25625541

RESUMEN

Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles.


Asunto(s)
Amidas/farmacología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Bazo/enzimología , Amidas/síntesis química , Amidas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/genética , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Pruebas de Mutagenicidad , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Bazo/efectos de los fármacos , Relación Estructura-Actividad
12.
PLoS One ; 7(5): e37207, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22623993

RESUMEN

A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Janus Quinasa 2/antagonistas & inhibidores , Policitemia Vera/tratamiento farmacológico , Animales , Western Blotting , Proliferación Celular/efectos de los fármacos , Ensayo de Unidades Formadoras de Colonias , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/uso terapéutico , Eritropoyetina/metabolismo , Citometría de Flujo , Humanos , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción STAT5/metabolismo
13.
Proc Natl Acad Sci U S A ; 101(33): 12048-53, 2004 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-15208404

RESUMEN

The cytochalasins are structurally complex natural products with a broad range of apparently unrelated effects in different biological systems. Different members of the family have variously demonstrated inhibitory activity toward the formation of actin filaments, toward the functioning of HIV protease, and toward the process of angiogenesis. The structural series is defined by a largely conserved, rigid bicyclic isoindolone core that is fused to a macrocyclic appendage. The latter structural component varies widely within the cytochalasins and seems to play an important role in the determination of biological activity. In this work, we describe the development of a convergent and enantioselective synthetic route to the cytochalasins that allows for the late-stage introduction of macrocyclic appendages of different sizes and constitutions. We illustrate the route with the synthesis of the 14-membered macrolactone cytochalasin B (1, an inhibitor of the formation of actin filaments) and the 11-membered macrocarbocyclic cytochalasin L-696,474 (2, an inhibitor of HIV protease) by using common precursors.


Asunto(s)
Citocalasina B/síntesis química , Citocalasinas/síntesis química , Química Orgánica/métodos , Citocalasina B/química , Citocalasinas/química , Isoindoles , Estructura Molecular , Estereoisomerismo
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