RESUMEN
Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178).
Asunto(s)
Proliferación Celular , Quinasa 4 Dependiente de la Ciclina , Inhibidores de Proteínas Quinasas , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Animales , Descubrimiento de Drogas , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Dosis-Respuesta a Droga , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Ratas , Ensayos de Selección de Medicamentos Antitumorales , Evaluación Preclínica de MedicamentosRESUMEN
As an orally effective benzimidazole anthelmintic agent, fenbendazole was not only widely used in agriculture and animal husbandry to prevent and treat parasites, but also shows anti-cancer effects against several types of cancer, exhibits anti-cancer effects in paclitaxel and doxorubicin-resistant cancer cells. However, fenbendazole's poor in water solubility (0.3 µg/mL), limits its clinical applications. Even great efforts were made toward increasing its water solubility, the results were not significant to reach anti-cancer drug delivery requirement (5-10 mg/mL). Through single factor and orthogonal strategy, many complex conditions were designed and used to prepare the complexes, the inclusion complex with methyl-ß-cyclodextrin with 29.2 % of inclusion rate and 89.5% of inclusion yield can increase drug's water solubility to 20.21 mg/mL, which is the best result so far. Its structure was confirmed by differential scanning calorimetry, scanning electron microscopic image, 1D and 2D NMR spectra in D2O. In its in vitro pharmacokinetic study, fenbendazole was 75% released in 15 min., in its in vivo pharmacokinetic study, the bio-availabilities of fenbendazole, its major metabolic anthelmintic agent oxfendazole and its minor metabolic anthelmintic agent oxfendazole were increased to 138%, 149% and 169% respectively, which would allow for fewer drug doses to achieve the same therapeutic effect and suggest that the complex can be used as a potential anticancer agent.
Asunto(s)
Fenbendazol , Solubilidad , beta-Ciclodextrinas , Fenbendazol/farmacocinética , Fenbendazol/uso terapéutico , Fenbendazol/química , Animales , beta-Ciclodextrinas/química , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Masculino , Antihelmínticos/farmacocinética , Antihelmínticos/química , Antihelmínticos/administración & dosificaciónRESUMEN
As a powerful imidazole antifungal drug, ketoconazole's low solubility (0.017 mg/mL), together with its odor and irritation, limited its clinical applications. The inclusion complex of ketoconazole with randomly methylated ß-cyclodextrin was prepared by using an aqueous solution method after cyclodextrin selection through phase solubility studies, complexation methods, and condition selection through single factor and orthogonal strategies. The complex was confirmed by FTIR (Fourier-transform infrared spectroscopy), DSC (differential scanning calorimetry), TGA (thermogravimetric analysis), SEM (scanning electron microscope images), and NMR (Nuclear magnetic resonance) studies. Through complexation, the water solubility of ketoconazole in the complex was increased 17,000 times compared with that of ketoconazole alone, which is the best result so far for the ketoconazole water solubility study. In in vitro pharmacokinetic studies, ketoconazole in the complex can be 100% released in 75 min, and in in vivo pharmacokinetic studies in dogs, through the complexation, the Cmax was increased from 7.56 µg/mL to 13.58 µg/mL, and the AUC0~72 was increased from 22.69 µgh/mL to 50.19 µgh/mL, indicating that this ketoconazole complex can be used as a more efficient potential new anti-fungal drug.
Asunto(s)
Antifúngicos , Cetoconazol , Solubilidad , beta-Ciclodextrinas , Cetoconazol/química , Cetoconazol/farmacocinética , Cetoconazol/farmacología , Cetoconazol/administración & dosificación , beta-Ciclodextrinas/química , Animales , Antifúngicos/farmacología , Antifúngicos/farmacocinética , Antifúngicos/química , Perros , Rastreo Diferencial de Calorimetría , Espectroscopía Infrarroja por Transformada de Fourier , MetilaciónRESUMEN
Albendazole is the preferred deworming drug and has strong insecticidal effects on human and animal helminth parasites, showing remarkable activity against hepatocellular carcinoma and colorectal cancer cells. However, it is classified as being in class II in the Biopharmaceutics Classification System due to its poor water solubility (0.2 mg/L) and high permeability, which make the clinical application of albendazole impractical. Through complexation with methyl-ß-cyclodextrin, as the best result so far, albendazole's water solubility was increased by 150,000 times, and albendazole could be 90% released during the first 10 min. In an in vivo pharmacokinetic study, the Cmax and Tmax of the active metabolized sulfoxide were changed from 2.81 µg/mL at 3 h to 10.2 µg/mL at 6 h and the AUC0-48 was increased from 50.72 hâµg/mL to 119.95 hâµg/mL, indicating that the inclusion complex obtained can be used as a new oral therapeutic anti-anthelmintic and anti-tumor agent formulation.
Asunto(s)
Antihelmínticos , Ciclodextrinas , Animales , Humanos , Albendazol/farmacocinética , Ciclodextrinas/farmacocinética , Solubilidad , Antihelmínticos/farmacocinética , AguaRESUMEN
Since griseofulvin was marketed as a non-polyene antifungal antibiotic drug in 1958, its poor water solubility has been an issue for its wide applications, and over the last sixty years, many attempts have been made to increase its water solubility; however, a significant result has yet to be achieved. Through supercritical carbon dioxide-assisted cyclodextrin complexation with the addition of a trace amount of water-soluble polymer surfactant, the griseofulvin inclusion complex with HP-γ-cyclodextrin was prepared and confirmed. The 1:2 ratio of griseofulvin and HP-γ-cyclodextrin in the complex was determined based on its NMR study. After complexation with HP-γ-cyclodextrin, griseofulvin's water solubility was increased 477 times compared with that of griseofulvin alone, which is the best result thus far. The complex showed 90% of griseofulvin release in vitro in 10 min, in an in vivo dog pharmacokinetic study; the Cmax was increased from 0.52 µg/mL to 0.72 µg/mL, AUC0-12 was increased from 1.55 µg·h/mL to 2.75 µg·h/mL, the clearance was changed from 51.78 L/kg/h to 24.16 L/kg/h, and the half-life time was changed from 0.81 h to 1.56 h, indicating the obtained griseofulvin complex can be a more effective drug than griseofulvin alone.
Asunto(s)
Griseofulvina , gamma-Ciclodextrinas , Animales , Perros , Solubilidad , Dióxido de Carbono , Agua , 2-Hidroxipropil-beta-Ciclodextrina/químicaRESUMEN
GST-HG131, a novel dihydroquinolizinone (DHQ) compound, has been shown to reduce circulating levels of HBsAg in animals. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetic profile of GST-HG131 in healthy Chinese subjects. This was a double-blind, randomized, placebo-controlled phase Ia clinical trial that was conducted in two parts. Part A was a single-ascending-dose (SAD; GST-HG131 10 30, 60, 100, 150, 200, 250 or 300 mg or placebo) study, which also assessed the food effect of GST-HG131 100 mg. Part B was a multiple-ascending-dose (MAD; GST-HG131 30, 60 or 100 mg or placebo BID) study. Tolerability assessments included adverse events, vital signs, 12-lead electrocardiogram, physical examination, and clinical laboratory tests. PK analyses were conducted in blood, urine, and fecal samples. Single doses of GST-HG131 ≤ 300 mg and multiple doses of GST-HG131 ≤ 60 mg were generally safe and well tolerated; however, multiple dosing was stopped at GST-HG131 100 mg, as pre-defined stopping rules specified in the protocol were met (Grade II drug related AEs of nausea and dizziness in >50% of subjects). In the SAD study, median tmax of GST-HG131 was 1-6 h, and t1/2 ranged from 3.88 h to 14.3 h. PK parameters were proportional to dose. Exposure was reduced after food intake. In the MAD study, steady-state was attained on day 4, and there was no apparent plasma accumulation of GST-HG131 on day 7 (Racc < 1.5). In conclusion, GST-HG131 exhibited an acceptable safety profile in healthy subjects at single doses ranging from 10-300 mg and multiple doses (BID) ranging from 30-60 mg, and the MAD doses (30 mg and 60 mg BID) that potentially meet the therapeutic AUC requirements. These findings imply GST-HG131 has potential as a therapeutic option for CHB infection. (This study has been registered at ClinicalTrials.gov under identifier NCT04499443.).
Asunto(s)
Virus de la Hepatitis B , Área Bajo la Curva , China , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , HumanosRESUMEN
Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a major health problem worldwide. The treatment for MDR-TB requires medications for a long duration (up to 20-24 months) with second-line drugs resulting in unfavorable outcomes. Nitroimidazoles are promising antimycobacterial agents known to inhibit both aerobic and anaerobic mycobacterial activity. Delamanid and pretomanid are two nitroimidazoles approved by the regulatory agencies for MDR-TB treatment. However, both agents possess unsatisfactory absorption and QTc prolongation. In our search for a safer nitroimidazole, we discovered JBD0131 (2). It exhibited excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo, improved PK and absorption, reduced QT prolongation potential of delamanid. JBD0131 is currently in clinical development in China for pulmonary tuberculosis (CTR20202308).
Asunto(s)
Mycobacterium tuberculosis , Nitroimidazoles , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis Pulmonar , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Humanos , Nitroimidazoles/farmacología , Nitroimidazoles/uso terapéutico , Oxazoles/farmacología , Oxazoles/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiologíaRESUMEN
Multidrug resistant tuberculosis (MDR-TB) remains a major human health challenge. Bedaquiline was approved in 2012 by the US FDA, and listed by WHO as a treatment for multidrug-resistant tuberculosis (MDR-TB) in 2018. However, the side effects of bedaquiline including the risk of unexplained mortality, QTc prolongation and hepatotoxicity limit its wide clinical use. Based on bedaquiline, we describe herein discovery and development of a novel diarylpyridine series, which led to identification of WX-081 (sudapyridine, 21l). It displayed excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo and low cytotoxicity; additionally WX-081 had excellent pharmacokinetic parameters in animals, better lung exposure and lower QTc prolongation potential compared to bedaquiline. WX-081 is currently under clinical phase II development (NCT04608955).
Asunto(s)
Síndrome de QT Prolongado , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Animales , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
We previously described the discovery of a novel indole series compounds as oral SERD for ER positive breast cancer treatment. Further SAR exploration focusing on substitutions on indole moiety of compound 12 led to the discovery of a clinical candidate LX-039. We report herein its profound anti-tumor activity, desirable ER antagonistic characteristics combined with favorable pharmacokinetic and preliminary safety properties. LX-039 is currently in clinical trial (NCT04097756).
Asunto(s)
Neoplasias de la Mama , Receptores de Estrógenos , Administración Oral , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ensayos Clínicos como Asunto , Receptor alfa de Estrógeno , Femenino , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Moduladores Selectivos de los Receptores de Estrógeno/farmacologíaRESUMEN
Chronic hepatitis B (CHB) remains a significant health challenge worldwide. The current treatments for CHB achieve less than 10% cure rates, majority of the patients are on therapy for life. Therefore, cure of CHB is a high unmet medical need. HBV surface antigen (HBsAg) loss and seroconversion are considered as the key for the cure. RG7834 is a novel, orally bioavailable small molecule reported to reduce HBV antigens. Based on RG7834 chemistry, we designed and discovered a series of dihydrobenzopyridooxazepine (DBP) series of HBV antigen inhibitors. Extensive SAR studies led us to GST-HG131 with excellent reduction of HBV antigens (both HBsAg and HBeAg) in vitro and in vivo. GST-HG131 improved safety in rat toxicology studies over RG7834. The promising inhibitory activity, together with animal safety enhancement, merited GST-HG131 progressed into clinical development in 2020 (NCT04499443).
Asunto(s)
Hepatitis B Crónica , Hepatitis B , Animales , Ratas , Antígenos de Superficie , Antivirales/farmacología , Antivirales/uso terapéutico , ADN Viral , Hepatitis B/tratamiento farmacológico , Antígenos e de la Hepatitis B/uso terapéutico , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Hepatitis B Crónica/tratamiento farmacológicoRESUMEN
ALK gene rearrangements are oncogenic drivers in approximately 5% of NSCLC. Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which led to the identification of WX-0593 (16a) as a potent ALK inhibitor. WX-0593 inhibited the activity of both wild type and resistant mutants of ALK in vitro, showed strong antitumor activity in a crizotinib-resistant mouse PDX model. WX-0593 is currently under development in phase II/III clinical trials.
Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Crizotinib/farmacología , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Proteínas Tirosina Quinasas ReceptorasRESUMEN
This study aimed to evaluate the antimicrobial activity of the novel monosulfactam 0073 against multidrug-resistant Gram-negative bacteria in vitro and in vivo and to characterize the mechanisms underlying 0073 activity. The in vitro activities of 0073, aztreonam, and the combination with avibactam were assessed by MIC and time-kill assays. The safety of 0073 was evaluated using 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and acute toxicity assays. Murine thigh infection and pneumonia models were employed to define in vivo efficacy. A penicillin-binding protein (PBP) competition assay and confocal microscopy were conducted. The inhibitory action of 0073 against ß-lactamases was evaluated by the half-maximal inhibitory concentration (IC50), and resistance development was evaluated via serial passage. The monosulfactam 0073 showed promising antimicrobial activity against Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii isolates producing metallo-ß-lactamases (MBLs) and serine ß-lactamases. In preliminary experiments, compound 0073 exhibited safety both in vitro and in vivo In the murine thigh infection model and the pneumonia models in which infection was induced by P. aeruginosa and Klebsiella pneumoniae, 0073 significantly reduced the bacterial burden. Compound 0073 targeted several PBPs and exerted inhibitory effects against some serine ß-lactamases. Finally, 0073 showed a reduced propensity for resistance selection compared with that of aztreonam. The novel monosulfactam 0073 exhibited increased activity against ß-lactamase-producing Gram-negative organisms compared with the activity of aztreonam and showed good safety profiles both in vitro and in vivo The underlying mechanisms may be attributed to the affinity of 0073 for several PBPs and its inhibitory activity against some serine ß-lactamases. These data indicate that 0073 represents a potential treatment for infections caused by ß-lactamase-producing multidrug-resistant bacteria.
Asunto(s)
Antibacterianos , Compuestos de Azabiciclo , beta-Lactamasas/farmacología , Animales , Antibacterianos/farmacología , Aztreonam , Enterobacteriaceae , Ratones , Pruebas de Sensibilidad Microbiana , Inhibidores de beta-LactamasasRESUMEN
Most estrogen receptor positive (ER +) breast cancers depend on ER signaling pathway to develop. Clinical application of SERD fulvestrant effectively degraded ER, blocked its function and prolonged progression free survival of ER + breast cancer patients. However, current SERD suffers from limited bioavailability, therefore is given as intramuscular (IM) injection. In this paper, we report herein a novel indole series compounds with nanomolar range ER degradation potencies and oral systemic exposures. Selected compounds suppressed tumor growth in vivo in ER + MCF7 breast cancer CDX model via p.o. administration. All those data supported further optimizations of this analog to develop preclinical candidate as oral SERD for ER + breast cancer's treatment.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Diseño de Fármacos , Indoles/farmacología , Receptores de Estrógenos/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Indoles/administración & dosificación , Indoles/síntesis química , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Receptores de Estrógenos/metabolismo , Relación Estructura-ActividadRESUMEN
The introductions of the bicyclic 4-nitroimidazole and the oxazolidinone classes of antimicrobial agents represented the most significant advancements in the infectious disease area during the past two decades. Pretomanid, a bicyclic 4-nitroimidazole, and linezolid, an oxazolidinone, are also part of a combination regimen approved recently by the US Food and Drug Administration for the treatment of pulmonary, extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) Mycobacterium tuberculosis (TB). To identify new antimicrobial agents with reduced propensity for the development of resistance, a series of dual-acting nitroimidazole-oxazolidinone conjugates were designed, synthesized and evaluated for their antimicrobial activity. Compounds in this conjugate series have shown synergistic activity against a panel of anaerobic bacteria, including those responsible for serious bacterial infections.
Asunto(s)
Antituberculosos/farmacología , Nitroimidazoles/farmacología , Oxazolidinonas/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Antituberculosos/química , Bacterias Anaerobias/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Linezolid/química , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Nitroimidazoles/química , Oxazolidinonas/química , Tuberculosis Resistente a Múltiples Medicamentos/microbiologíaRESUMEN
New analogues of antitubercular drug Delamanid were prepared, seeking drug candidates with enhanced aqueous solubility and high efficacy. The strategy involved replacement of phenoxy linker proximal to the 2-nitroimidazooxazole of Delamanid by piperidine fused 5 or 6-membered ring heterocycles (ring A). The new compounds were all more hydrophilic than Delamanid, and several class of analogues showed remarkable activities against M. bovis. And among these series, the tetrahydro-naphthyridine-linked nitroimidazoles displayed excellent antimycobacterial activity against both replicating (MABA) and nonreplicating (LORA) M. tb H37Rv and low cytotoxicity. Compared to Delamanid, these new compounds (6, 7, 45) demonstrated dramatically improved physicochemical properties and are suitable for further in vitro and in vivo evaluation.
Asunto(s)
Antituberculosos/química , Oxazoles/química , Animales , Antituberculosos/síntesis química , Antituberculosos/farmacología , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Nitroimidazoles/farmacología , Oxazoles/síntesis química , Oxazoles/farmacología , Permeabilidad/efectos de los fármacos , Solubilidad , Relación Estructura-Actividad , Células VeroRESUMEN
The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.
Asunto(s)
Antituberculosos/farmacología , Leucina-ARNt Ligasa/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Administración Oral , Animales , Antituberculosos/administración & dosificación , Antituberculosos/química , Antituberculosos/farmacocinética , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Leucina-ARNt Ligasa/química , Leucina-ARNt Ligasa/genética , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos , Pruebas de Sensibilidad Microbiana , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/genética , Mycobacterium tuberculosis/genética , Inhibidores de la Síntesis de la Proteína/administración & dosificación , Inhibidores de la Síntesis de la Proteína/química , Inhibidores de la Síntesis de la Proteína/farmacocinética , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico , Células VeroRESUMEN
Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (410 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , L-Lactato Deshidrogenasa/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Perros , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , L-Lactato Deshidrogenasa/metabolismo , Células de Riñón Canino Madin DarbyRESUMEN
The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.
Asunto(s)
Hipoglucemiantes/síntesis química , PPAR alfa/agonistas , PPAR gamma/agonistas , Pirrolidinas/química , Animales , Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Femenino , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Ligandos , Ratones , Ratones Obesos , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/uso terapéutico , Estereoisomerismo , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
A series of 3,6-disubstituted dihydropyrones were identified as inhibitors of human lactate dehydrogenase (LDH)-A. Structure activity relationships were explored and a series of 6,6-spiro analogs led to improvements in LDHA potency (IC50 <350 nM). An X-ray crystal structure of an improved compound bound to human LDHA was obtained and it illustrated additional opportunities to enhance the potency of these compounds, resulting in the identification of 51 (IC50=30 nM).
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , L-Lactato Deshidrogenasa/antagonistas & inhibidores , Pironas/síntesis química , Pironas/farmacología , Sitios de Unión , Cristalografía por Rayos X , Humanos , L-Lactato Deshidrogenasa/metabolismo , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50=1.7 µM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.18 µM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F=45%).