RESUMEN
Natural products remain one of the major sources of coveted, biologically active compounds. Each isolated compound undergoes biological testing, and its structure is usually established using a set of spectroscopic techniques (NMR, MS, UV-IR, ECD, VCD, etc.). However, the number of erroneously determined structures remains noticeable. Structure revisions are very costly, as they usually require extensive use of spectroscopic data, computational chemistry, and total synthesis. The cost is particularly high when a biologically active compound is resynthesized and the product is inactive because its structure is wrong and remains unknown. In this paper, we propose using Computer-Assisted Structure Elucidation (CASE) and Density Functional Theory (DFT) methods as tools for preventive verification of the originally proposed structure, and elucidation of the correct structure if the original structure is deemed to be incorrect. We examined twelve real cases in which structure revisions of natural products were performed using total synthesis, and we showed that in each of these cases, time-consuming total synthesis could have been avoided if CASE and DFT had been applied. In all described cases, the correct structures were established within minutes of using the originally published NMR and MS data, which were sometimes incomplete or had typos.
RESUMEN
Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteínas Quinasas/química , Pirazinas/química , Agammaglobulinemia Tirosina Quinasa/metabolismo , Animales , Artritis Experimental/tratamiento farmacológico , Sitios de Unión , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Imidazoles/metabolismo , Imidazoles/uso terapéutico , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/metabolismo , Pirazinas/uso terapéutico , Ratas , Ratas Wistar , Relación Estructura-Actividad , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
Correction for 'The medicinal chemist's toolbox for late stage functionalization of drug-like molecules' by Tim Cernak et al., Chem. Soc. Rev., 2016, 45, 546-576.
RESUMEN
The advent of modern C-H functionalization chemistries has enabled medicinal chemists to consider a synthetic strategy, late stage functionalization (LSF), which utilizes the C-H bonds of drug leads as points of diversification for generating new analogs. LSF approaches offer the promise of rapid exploration of structure activity relationships (SAR), the generation of oxidized metabolites, the blocking of metabolic hot spots and the preparation of biological probes. This review details a toolbox of intermolecular C-H functionalization chemistries with proven applicability to drug-like molecules, classified by regioselectivity patterns, and gives guidance on how to systematically develop LSF strategies using these patterns and other considerations. In addition, a number of examples illustrate how LSF approaches have been used to impact actual drug discovery and chemical biology efforts.
RESUMEN
We report the development and implementation of a cheminformatics tool which aids in the design of compounds during exploratory chemistry and lead optimization. The Heterocyclic Regioisomer Enumeration and MDDR Search (HREMS) tool allows medicinal chemists to build greater structural diversity into their synthetic planning by enabling a systematic, automated enumeration of heterocyclic regioisomers of target structures. To help chemists overcome biases arising from past experience or synthetic accessibility, the HREMS tool further provides statistics on clinical testing for each enumerated regioisomer substructure using an automated search of a commercial database. Ready access to this type of information can help chemists make informed choices on the targets they will pursue being mindful of past experience with these structures in drug development. This tool and its components can be incorporated into other cheminformatics workflows to leverage their capabilities in triaging and in silico compound enumeration.
Asunto(s)
Diseño de Fármacos , Compuestos Heterocíclicos/química , Informática/métodos , Bases de Datos Farmacéuticas , Reproducibilidad de los Resultados , EstereoisomerismoRESUMEN
N-type calcium channels (Ca(v)2.2) have been shown to play a critical role in pain. A series of low molecular weight 2-aryl indoles were identified as potent Ca(v)2.2 blockers with good in vitro and in vivo potency.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo N/metabolismo , Indoles/uso terapéutico , Dolor/tratamiento farmacológico , Animales , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/farmacología , Perros , Haplorrinos , Humanos , Indoles/farmacocinética , Indoles/farmacología , RatasRESUMEN
Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Enfermedad Coronaria/tratamiento farmacológico , Oxazolidinonas/uso terapéutico , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/toxicidad , Perros , Humanos , Macaca mulatta , Ratones Endogámicos C57BL , Estructura Molecular , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacocinética , Oxazolidinonas/toxicidad , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.
Asunto(s)
Neuralgia/tratamiento farmacológico , Pirazoles/química , Pirazoles/uso terapéutico , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismo , Animales , Perros , Haplorrinos , Humanos , Microsomas Hepáticos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.7 , Pirazoles/farmacocinética , Pirazoles/farmacología , Ratas , Bloqueadores de los Canales de Sodio/farmacocinética , Bloqueadores de los Canales de Sodio/farmacología , Relación Estructura-ActividadRESUMEN
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency.
Asunto(s)
Neuralgia/tratamiento farmacológico , Oxazoles/uso terapéutico , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismo , Tiazoles/uso terapéutico , Animales , Perros , Humanos , Imidazoles/química , Imidazoles/metabolismo , Imidazoles/farmacología , Imidazoles/uso terapéutico , Microsomas Hepáticos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.7 , Oxazoles/química , Oxazoles/metabolismo , Oxazoles/farmacología , Ratas , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Tiazoles/química , Tiazoles/metabolismo , Tiazoles/farmacologíaRESUMEN
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.
Asunto(s)
Compuestos de Bifenilo/química , Neuralgia/tratamiento farmacológico , Pirazoles/química , Bloqueadores de los Canales de Sodio/química , Canales de Sodio/química , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/uso terapéutico , Perros , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Actividad Motora/efectos de los fármacos , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Ratas , Bloqueadores de los Canales de Sodio/farmacocinética , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismoRESUMEN
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 , HumanosRESUMEN
We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
Asunto(s)
Derivados del Benceno/síntesis química , Derivados del Benceno/farmacología , Inhibidores de Histona Desacetilasas , Modelos Moleculares , Derivados del Benceno/química , Sitios de Unión/efectos de los fármacos , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Estructura Molecular , Isoformas de Proteínas , Proteínas Represoras , Relación Estructura-ActividadRESUMEN
Bismuth(III) acetate is a safe, inexpensive, and selective facilitator of sequential protodeboronations, which when used in conjunction with Ir-catalyzed borylations allows access to a diversity of borylated indoles. The versatility of combining Ir-catalyzed borylations with Bi(III)-catalyzed protodeboronation is demonstrated by selectively converting 6-fluoroindole into products with Bpin groups at the 4-, 5-, 7-, 2,7-, 4,7-, 3,5-, and 2,4,7-positions and the late-stage functionalization of sumatriptan.
Asunto(s)
Acetatos/química , Bismuto/química , Compuestos de Boro/química , Indoles/química , Catálisis , Estructura MolecularRESUMEN
An efficient synthesis of the truncated 3"-aldehyde (3) from nodulisporic acid A (1) under mild conditions is described. Further oxidation of 3 to 3"-carboxylic acid (4) and its subsequent oxidative degradation produced 1"-aldehyde (5). These new derivatives are versatile intermediates for the preparation of new, side chain modified derivatives of nodulisporic acid A. [reaction: see text]
Asunto(s)
Aldehídos/síntesis química , Ácidos Carboxílicos/síntesis química , Indoles/química , Insecticidas/química , Indicadores y Reactivos , Oxidación-ReducciónRESUMEN
Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA permitted a one-carbon homologation to the 6" register. These efforts identified new analogues with significant flea activity and illustrated the biological significance of unsaturation at the 1",2" register.