Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
1.
Nature ; 558(7710): E1, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29769713

RESUMEN

In the originally published version of this Letter, the authors Arthur F. Kluge, Michael A. Patane and Ce Wang were inadvertently omitted from the author list. Their affiliations are: I-to-D, Inc., PO Box 6177, Lincoln, Massachusetts 01773, USA (A.F.K.); Mitobridge, Inc. 1030 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (M.A.P.); and China Novartis Institutes for BioMedical Research, No. 4218 Jinke Road, Zhangjiang Hi-Tech Park, Pudong District, Shanghai 201203, China (C.W.). These authors contributed to the interpretation of results and design of compounds. In addition, author 'Edward A. Kesicki' was misspelled as 'Ed Kesicki'. These errors have been corrected online.

2.
Bioorg Med Chem Lett ; 30(4): 126928, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31889664

RESUMEN

One of the most commonly used strategies to reduce hERG (human ether-a-go-go) activity in the drug candidates is introduction of a carboxylic acid group. During the optimization of PPARδ modulators, some of the compounds containing a carboxylic acid were found to inhibit the hERG channel in a patch clamp assay. By modifying the basicity of the imidazole core, potent and selective PPARδ modulators that do not inhibit hERG channel were identified. Some of the modulators have excellent pharmacokinetic profiles in mice.


Asunto(s)
Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , PPAR delta/química , Bloqueadores de los Canales de Potasio/química , Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/metabolismo , Semivida , Humanos , Cinética , PPAR delta/genética , PPAR delta/metabolismo , Bloqueadores de los Canales de Potasio/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Relación Estructura-Actividad , Activación Transcripcional/efectos de los fármacos
3.
Bioorg Med Chem Lett ; 28(3): 533-536, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29275935

RESUMEN

Compound 1 regulates significantly fewer genes than the PPARδ modulator, GW501516. Both compounds are efficacious in a thermal injury model of muscle regeneration. The restricted gene profile of 1 relative to GW501516 suggests that 1 may be pharmacoequivalent to GW501516 with fewer PPAR-related safety concerns.


Asunto(s)
PPAR delta/metabolismo , Tiazoles/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Ratas , Relación Estructura-Actividad
4.
Bioorg Med Chem Lett ; 27(23): 5230-5234, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29103972

RESUMEN

Optimization of benzamide PPARδ modulator 1 led to (E)-6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)-4-methylhex-4-enoic acid (18), a potent selective PPARδ modulator with significantly improved exposure in multiple species following oral administration.


Asunto(s)
Benzamidas/farmacocinética , Administración Oral , Animales , Benzamidas/administración & dosificación , Benzamidas/sangre , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intravenosas , Macaca fascicularis , Masculino , Ratones , Estructura Molecular , Ratas Wistar , Relación Estructura-Actividad
5.
Ophthalmology ; 119(1): 66-73, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22115712

RESUMEN

PURPOSE: Determine safe, effective, iontophoretic dose(s) of EGP-437 (dexamethasone phosphate formulated for iontophoresis) in patients with noninfectious anterior uveitis; evaluate systemic drug exposures. DESIGN: Prospective, phase I/II, multicenter, double-masked, parallel group, randomized clinical trial. PARTICIPANTS: Forty outpatients with anterior uveitis. METHODS: Forty of 42 randomized patients received an iontophoresis treatment in 1 qualifying eye and completed the study. Patients were randomized into 1 of 4 iontophoresis dose groups (1.6, 4.8, 10.0, or 14.0 mA-min), treated with EGP-437 via the EyeGate II Delivery System (EGDS), and followed until day 28. MAIN OUTCOME MEASURES: The main outcome measures were anterior chamber cell (ACC) scores at days 14 and 28; time to ACC score of zero; proportion of patients with an ACC score reduction from baseline of ≥ 0.5 at day 28; mean change from baseline in ACC score at day 28; and the systemic exposures of dexamethasone and dexamethasone phosphate after EGP-437 treatment with the EGDS. RESULTS: After a single EGP-437 treatment, 19 of 40 patients (48%) achieved an ACC score of zero at day 14. By day 28, 24 of 40 patients (60%) achieved an ACC score of zero. A Kaplan-Meier analysis demonstrated that the 1.6 mA-min dose was the most effective and revealed an inverse dose response; median days to an ACC score of zero were 11.5 days in the 1.6 mA-min group versus 31 days in the 14.0 mA-min group. Twenty-six patients (65%) had an ACC score reduction from baseline of ≥ 0.5 at day 28. The mean change in ACC score from baseline to day 28 was -2.14 with a median of -2.00. Throughout the study, the mean intraocular pressure remained within normal range and mean best-corrected visual acuity at 4 meters remained relatively stable. Most adverse events were mild; no serious adverse events were reported. Pharmacokinetics results showed low short-term systemic exposure to dexamethasone after iontophoresis; no nonocular systemic corticosteroid-mediated effects were observed. CONCLUSIONS: Approximately two thirds of the patients reached an ACC score of zero within 28 days, after only receiving 1 iontophoresis treatment. The lower doses seemed to be the most effective, and treatments were well-tolerated. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.


Asunto(s)
Dexametasona/análogos & derivados , Glucocorticoides/administración & dosificación , Iontoforesis , Uveítis Anterior/tratamiento farmacológico , Adulto , Anciano , Dexametasona/administración & dosificación , Método Doble Ciego , Sistemas de Liberación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Uveítis Anterior/fisiopatología , Adulto Joven
6.
Bioorg Med Chem Lett ; 21(11): 3210-5, 2011 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-21550238

RESUMEN

Imidazole analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and evaluated for gram positive bacteria growth inhibition. A recently reported, copper-mediated synthesis was exploited to prepare 4-thiazolyl imidazole analogs of 1. The synthesis described represents a structurally complex, natural product-based application of this recently reported synthetic methodology. In addition, the biological evaluation of the imidazole-based analogs further define the SAR of the 4-aminothiazolyl-based antibacterial template.


Asunto(s)
Aminas/síntesis química , Antibacterianos , Bacterias Grampositivas/efectos de los fármacos , Imidazoles/química , Péptidos Cíclicos/química , Tiazoles/síntesis química , Aminas/química , Aminas/farmacología , Antibacterianos/síntesis química , Antibacterianos/farmacología , Cobre/química , Escherichia coli/efectos de los fármacos , Imidazoles/síntesis química , Imidazoles/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos Cíclicos/farmacología , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología
8.
ACS Med Chem Lett ; 9(9): 935-940, 2018 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-30258544

RESUMEN

The X-ray structure of the previously reported PPARδ modulator 1 bound to the ligand binding domain (LBD) revealed that the amide moiety in 1 exists in the thermodynamically disfavored cis-amide orientation. Isosteric replacement of the cis-amide with five-membered heterocycles led to the identification of imidazole 17 (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested in vivo in mice and in vitro in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); 17 altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients.

9.
J Med Chem ; 59(14): 6920-8, 2016 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-27355833

RESUMEN

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) provided access to analogues in the Northern region (C2-C10). Selective hydrolysis of the C10 amide of lead compound 2 and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., 3) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster C. difficile models of disease. Optimal efficacy in the hamster model of C. difficile was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility.


Asunto(s)
Antibacterianos/farmacología , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/tratamiento farmacológico , Péptidos Cíclicos/farmacología , Tiazoles/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Cricetinae , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Solubilidad , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química
10.
J Med Chem ; 47(7): 1602-4, 2004 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-15027849

RESUMEN

The melanocortin 4 receptor (MC4R) plays an important role in body weight regulation and energy homeostasis. Administration of peptidic MC4R antagonists (usually by intracerebro ventricular injection) has been shown in the literature to increase body weight and/or food intake in several rodent models. We report here the identification of a novel nonpeptidic MC4R antagonist and its effects on tumor-induced weight loss in mice following peripheral administration.


Asunto(s)
Benzamidinas/síntesis química , Emaciación/tratamiento farmacológico , Imidazoles/síntesis química , Neoplasias/complicaciones , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Administración Cutánea , Animales , Benzamidinas/química , Benzamidinas/farmacología , Emaciación/etiología , Imidazoles/química , Imidazoles/farmacología , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Trasplante Heterólogo
11.
J Ocul Pharmacol Ther ; 29(8): 760-9, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23844757

RESUMEN

PURPOSE: To evaluate the toxicokinetics and tolerability (local ocular and general toxicity) of the anti-inflammatory agent, dexamethasone phosphate (a prodrug of dexamethasone) delivered to the eye in rabbits by transscleral iontophoresis. METHODS: Female rabbits (n=6/group) received dexamethasone phosphate (40 mg/mL ophthalmic solution, EGP-437) transsclerally to the right eye (OD) using the Eyegate(®) II ocular iontophoresis delivery system once biweekly for 24 consecutive weeks at current doses of 10, 14, and 20 mA-min and current levels up to, and including -4 mA for 3.5-5 min. The study included 2 control groups (n=6/group): (1) a noniontophoresis control [an ocular applicator-loaded citrate buffer (placebo) without current] and (2) an iontophoresis control (a citrate buffer plus cathode iontophoresis at 20 mA-min, -4 mA for 5 min). Recoverability was evaluated 4 weeks following the last dose in 2 animals per group. The left eye (OS) was untreated and served as an internal control for each animal. Ocular and general safety of dexamethasone phosphate and dexamethasone were assessed. Other evaluations included toxicokinetics, ophthalmic examinations, intraocular pressure (IOP) measurements, electroretinographs, clinical observations, body weight, hematology and serum chemistry, gross necropsy, organ weight, and microscopic histopathology. RESULTS: The biweekly transscleral iontophoresis with either the citrate buffer or dexamethasone phosphate at cathodic doses up to, and including 20 mA-min and currents up to, and including -4 mA for 24 weeks was well-tolerated. Transient signs of conjunctival hyperemia and chemosis, mild corneal opacity, and fluorescein staining of the cornea were noted and attributed to expected ocular reactions to the temporary placement of the ocular applicator and application of iontophoresis. There were no dexamethasone phosphate-, dexamethasone-, or iontophoresis-related effects on IOP, electroretinography, or histopathology. Reductions in body weight gain, anemia, decreased leukocyte and lymphocyte counts, compromised liver function, enlarged liver, and reduced spleen weight were consistent with systemic corticosteroid-mediated pharmacology, repeated use of anesthesia, stress, and sedentariness, and unlikely to be related to iontophoresis application. CONCLUSIONS: The results of this investigation suggest that repeated transscleral iontophoresis with dexamethasone phosphate may be safe for use as a treatment for inflammatory ocular disorders that require prolonged and/or repeated corticosteroid therapy.


Asunto(s)
Dexametasona/análogos & derivados , Sistemas de Liberación de Medicamentos , Ojo/efectos de los fármacos , Glucocorticoides/efectos adversos , Iontoforesis , Animales , Peso Corporal/efectos de los fármacos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Dexametasona/sangre , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Ojo/metabolismo , Ojo/patología , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/sangre , Soluciones Oftálmicas , Tamaño de los Órganos/efectos de los fármacos , Especificidad de Órganos , Conejos
12.
J Med Chem ; 55(15): 6934-41, 2012 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-22812377

RESUMEN

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of 1 included removing the C2-C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to 1. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of 2, a structurally simplified and chemically stable analogue of 1 which retained potent antibiotic activity.


Asunto(s)
Antibacterianos/síntesis química , Péptidos Cíclicos/síntesis química , Tiazoles/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Clostridioides difficile/efectos de los fármacos , Cristalografía por Rayos X , Enterococcus/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/biosíntesis , Proteínas de Escherichia coli/química , Femenino , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Factor Tu de Elongación Peptídica/química , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Inhibidores de la Síntesis de la Proteína/síntesis química , Inhibidores de la Síntesis de la Proteína/química , Inhibidores de la Síntesis de la Proteína/farmacología , Ratas , Ratas Sprague-Dawley , Staphylococcus aureus/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología , Transcripción Genética/efectos de los fármacos
13.
J Med Chem ; 55(5): 2376-87, 2012 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-22315981

RESUMEN

Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.


Asunto(s)
Antibacterianos/síntesis química , Clostridioides difficile/efectos de los fármacos , Enterocolitis Seudomembranosa/tratamiento farmacológico , Tiazoles/síntesis química , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Cricetinae , Cristalografía por Rayos X , Enterococcus/efectos de los fármacos , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/química , Femenino , Masculino , Mesocricetus , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Factor Tu de Elongación Peptídica/antagonistas & inhibidores , Factor Tu de Elongación Peptídica/química , Ratas , Ratas Sprague-Dawley , Solubilidad , Staphylococcus aureus/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/farmacocinética , Agua
14.
Clin Ophthalmol ; 5: 633-43, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21629568

RESUMEN

PURPOSE: To assess safety and efficacy of EGP-437 (dexamethasone phosphate 40 mg/mL [DP]) in dry eye patients. METHODS: The study employed a prospective, single-center, double-masked design utilizing a Controlled Adverse Environment (CAE). Patients (n = 103) with confirmed signs and symptoms of dry eye syndrome were randomized into 1 of 3 iontophoresis treatment groups: 7.5 mA-min at 2.5 mA (DP 7.5, n = 41); 10.5 mA-min at 3.5 mA (DP 10.5, n = 37); or 10.5 mA-min at 3.5 mA (placebo, n = 25). Three CAE visits and 4 follow-up visits occurred over 3 weeks. Patients meeting enrollment criteria received iontophoresis in both eyes after the second CAE exposure (visit 3) and before the third CAE exposure (visit 5). Primary efficacy endpoints were corneal staining and ocular discomfort. Secondary endpoints included tear film break-up time, ocular protection index (OPI), and symptomatology. RESULTS: The DP 7.5 and DP 10.5 treatment groups showed statistically significant improvements in signs and symptoms of dry eye at various time points; however, the primary endpoints were not achieved. The DP 7.5 treatment group exhibited statistically significant improvements in corneal staining (when comparing the differences between study entry and exit, 3 weeks, P = 0.039), OPI (immediately following the second treatment, P = 0.048) and ocular discomfort at follow-up visits (a week after the first treatment, P = 0.032; 24 hours after the second treatment, P = 0.0032). Treatment-emergent adverse events (AEs) were experienced by 87% of patients and were consistent across all treatment groups. Most AEs were mild and no severe AEs were observed. CONCLUSION: Ocular iontophoresis of EGP-437 demonstrated statistically and clinically significant improvements in signs and symptoms of dry eye syndrome within a CAE model.

15.
J Med Chem ; 54(7): 2517-21, 2011 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-21405087

RESUMEN

4-Aminothiazolyl analogues of the antibacterial natural product GE2270 A (1) were designed, synthesized, and evaluated for gram positive bacteria growth inhibition. The aminothiazole-based chemical template was evaluated for chemical stability, and its decomposition revealed a novel, structurally simplified, des-thiazole analogue of 1. Subsequent stabilization of the 4-aminothiazolyl functional motif was achieved and initial structure activity relationships defined.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Descubrimiento de Drogas , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Tiazoles/química , Antibacterianos/síntesis química , Bacterias/efectos de los fármacos , Estabilidad de Medicamentos , Pruebas de Sensibilidad Microbiana , Péptidos Cíclicos/síntesis química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacología
16.
J Med Chem ; 54(23): 8099-109, 2011 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-21999529

RESUMEN

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.


Asunto(s)
Antibacterianos/síntesis química , Ácidos Carboxílicos/síntesis química , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Péptidos Cíclicos/síntesis química , Tiazoles/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Área Bajo la Curva , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Cristalografía por Rayos X , Farmacorresistencia Bacteriana , Femenino , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/genética , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Mutación , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Ratas , Ratas Sprague-Dawley , Sepsis/tratamiento farmacológico , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología
17.
J Control Release ; 147(2): 225-31, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20655965

RESUMEN

The fundamental understanding of ocular drug delivery using iontophoresis is not at the same level as that for transdermal electrotransport. Research has therefore been undertaken to characterise the electrical properties of the sclera (charge, permselectivity, and isoelectric point (pI)) and to determine the basics of iontophoretic transport of model neutral, cationic, and anionic species (respectively, mannitol, timolol, and dexamethasone phosphate). Like the skin, the sclera supports a net negative charge under physiological pH conditions and has a pI between 3.5 and 4. Equally, the principles of trans-scleral iontophoretic transport of low molecular weight compounds are consistent with those observed for skin. Iontophoretic delivery of timolol and dexamethasone phosphate was proportional to applied current and drug concentration, and trans-scleral iontophoresis in rabbits led to enhanced intraocular levels of these compounds compared to passive delivery. The behaviour of higher molecular weight species such as peptide drugs and other biopharmaceuticals (e.g., proteins and oligonucleotides) has not been fully characterised. Further work has been undertaken, therefore, to examine the trans-scleral iontophoresis of vancomycin, a glycopeptide antibiotic with a relatively high molecular weight of 1448 Da. It was indeed possible to deliver vancomycin by iontophoresis but trans-scleral transport did not increase linearly with either increasing current density or peptide concentration.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Iontoforesis , Preparaciones Farmacéuticas/administración & dosificación , Esclerótica/metabolismo , Animales , Transporte Biológico , Cromatografía Líquida de Alta Presión , Dexametasona/administración & dosificación , Dexametasona/análogos & derivados , Dexametasona/química , Dexametasona/farmacocinética , Sistemas de Liberación de Medicamentos/instrumentación , Electrodos , Diseño de Equipo , Femenino , Técnicas In Vitro , Manitol/administración & dosificación , Manitol/química , Manitol/farmacocinética , Peso Molecular , Preparaciones Farmacéuticas/química , Conejos , Espectrometría de Masas en Tándem , Timolol/administración & dosificación , Timolol/química , Timolol/farmacocinética , Vancomicina/administración & dosificación , Vancomicina/química , Vancomicina/farmacocinética
20.
J Biol Chem ; 279(17): 17996-8007, 2004 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-14754895

RESUMEN

The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence. ACE2 has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). To gain further insights into this enzyme, the first crystal structures of the native and inhibitor-bound forms of the ACE2 extracellular domains were solved to 2.2- and 3.0-A resolution, respectively. Comparison of these structures revealed a large inhibitor-dependent hinge-bending movement of one catalytic subdomain relative to the other ( approximately 16 degrees ) that brings important residues into position for catalysis. The potent inhibitor MLN-4760 ((S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino]-4-methylpentanoic acid) makes key binding interactions within the active site and offers insights regarding the action of residues involved in catalysis and substrate specificity. A few active site residue substitutions in ACE2 relative to ACE appear to eliminate the S(2)' substrate-binding subsite and account for the observed reactivity change from the peptidyl dipeptidase activity of ACE to the carboxypeptidase activity of ACE2.


Asunto(s)
Carboxipeptidasas/química , Secuencia de Aminoácidos , Aminoácidos/química , Enzima Convertidora de Angiotensina 2 , Sitios de Unión , Catálisis , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacología , Humanos , Imidazoles/farmacología , Leucina/análogos & derivados , Leucina/farmacología , Modelos Químicos , Modelos Moleculares , Datos de Secuencia Molecular , Peptidil-Dipeptidasa A , Unión Proteica , Conformación Proteica , Estructura Terciaria de Proteína , Receptores de Coronavirus , Receptores Virales/química , Homología de Secuencia de Aminoácido , Especificidad por Sustrato , Zinc/química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA