RESUMEN
SAR exploration at P1' using an anti-succinate-based macrocyclic hydroxamic acid as a template led to the identification of several bulky biphenylmethyl P1' derivatives which confer potent porcine TACE and anti-TNF-alpha cellular activities with high selectivity versus most of the MMPs screened. Our studies demonstrate for the first time that TACE has a larger S1' pocket in comparison to MMPs and that potent and selective TACE inhibitors can be achieved by incorporation of sterically bulky P1' residues.
Asunto(s)
Compuestos Heterocíclicos con 1 Anillo/síntesis química , Ácidos Hidroxámicos/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteínas ADAM , Proteína ADAM17 , Sitios de Unión , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Heterocíclicos con 1 Anillo/farmacología , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Lipopolisacáridos/farmacología , Modelos Moleculares , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Unión Proteica , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of =0.2 microM in whole blood assay (WBA). Although the P3' area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3' was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3', an N-methylamide at P4' provided the best cyclophane analogue, SL422 (WBA IC(50) = 0.22 microM, LPS-mouse ED(50) = 15 mg/kg, po), whereas a morpholinylamide at P4' afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBA IC(50) = 0.067 microM, LPS-mouse ED(50) = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with K(i) values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Ácidos Hidroxámicos/síntesis química , Lactamas/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteínas ADAM , Proteína ADAM17 , Administración Oral , Animales , Disponibilidad Biológica , Carbamatos/síntesis química , Carbamatos/química , Carbamatos/farmacocinética , Carbamatos/farmacología , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/farmacología , Técnicas In Vitro , Lactamas/química , Lactamas/farmacocinética , Lactamas/farmacología , Masculino , Ratones , Estereoisomerismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/análisisRESUMEN
A series of 2-(arylmethyl)pyridoisothiazolones is reported that inhibit the IL-1 beta induced breakdown of bovine nasal septum cartilage in an organ culture assay. The synthesis and preliminary SAR of these compounds are described. These compounds represent a novel, non-peptide lead series approach to the mediation of the chronic cartilage breakdown associated with arthritic disease. These compounds are relatively resistant to reductive metabolism by liver microsomal preparations and appear to inhibit cartilage breakdown by interfering with the proteolytic activation of matrix metalloproteinases.
Asunto(s)
Cartílago/metabolismo , Piridinas/farmacología , Tiazoles/farmacología , Animales , Bovinos , Indometacina/farmacología , Interleucina-1/antagonistas & inhibidores , Interleucina-1/metabolismo , Metaloproteinasa 3 de la Matriz , Metaloendopeptidasas/antagonistas & inhibidores , Metaloendopeptidasas/metabolismo , Microsomas/metabolismo , Naproxeno/farmacología , Tabique Nasal , Técnicas de Cultivo de Órganos , Oxidación-Reducción/efectos de los fármacos , Proteoglicanos/metabolismo , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
The synthesis, biological evaluation, and structure-activity relationships of a series of N-phenyl heteroaryl-fused isothiazolones are described. These isothiazolones have been shown to exhibit potent, dose-dependent inhibition of IL-1 beta-induced breakdown of proteoglycan in a cartilage organ culture assay. This effect is likely due to inhibition of MMP activation and a consequent reduction in MMP activity following IL-1 beta stimulation. Thus these compounds potentially represent simple, non-peptidic disease-modifying agents for the treatment of arthritic diseases. To examine the effects of structure on in vitro activity, three general features of the molecules were varied, substituents on the pendant N-phenyl group, the position of ring fusion to the isothiazolone, and substituents on the fused ring peri to the isothiazolone sulfur.
Asunto(s)
Cartílago/efectos de los fármacos , Cartílago/metabolismo , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Bovinos , Relación Dosis-Respuesta a Droga , Humanos , Interleucina-1/antagonistas & inhibidores , Interleucina-1/toxicidad , Isomerismo , Masculino , Metaloendopeptidasas/farmacología , Modelos Biológicos , Proteoglicanos/metabolismo , Piridinas/síntesis química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis, biological evaluation, and structure-activity relationships of a series of 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols are described. These compounds show potent dose-dependent topical antiinflammatory activity in murine models of skin inflammation. This effect is likely due to inhibition of cytochrome P450 and consequent reduction in levels of 12R-HETE in the skin. These compounds were examined for their ability to inhibit the oxidative metabolism of arachidonic acid; they specifically inhibit the formation of prostacyclins in mouse macrophages. To study the effects of structure on the in vivo activity, three general features of the molecules were varied: the position of attachment of the pyridine nucleus (A), the second aromatic residue (B), and the nitrogen base on the ethanol chain (C). 1-[4-(4-Pyridyl)phenyl]-1-(4-fluorophenyl)-2- imidazolylethanol (2a, DuP 983) shows a very attractive profile of antiinflammatory activity and has been selected for clinical evaluation as a topical antiinflammatory agent.
Asunto(s)
Antiinflamatorios/síntesis química , Imidazoles/síntesis química , Piridinas/síntesis química , Administración Tópica , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ácido Araquidónico , Calcimicina , Inhibidores de la Ciclooxigenasa/farmacología , Dermatitis/tratamiento farmacológico , Dermatitis/etiología , Edema/inducido químicamente , Edema/tratamiento farmacológico , Imidazoles/farmacología , Imidazoles/uso terapéutico , Inhibidores de la Lipooxigenasa/farmacología , Masculino , Ratones , Estructura Molecular , Fosfolipasas A/antagonistas & inhibidores , Piridinas/farmacología , Piridinas/uso terapéutico , Relación Estructura-Actividad , Acetato de TetradecanoilforbolRESUMEN
An electron microscope examination was carried out on the lungs of 11 pocket mice (Perognathus longimembris) that breathed oxygen at 10 psi or 12 psi partial pressure over a period of 7 d, at the end of which time they were decompressed to sea-level O2 pressure, either suddenly or in 30, 60, or 90 min. Vesiculation was noted in the endothelium of the alveolarcapillary wall in most of the animals and, occasionally, blebbing. Some mitochrondria were swollen in a few of the animals. Alveolar exudate was, in general, sparse. Compared with the lungs of other rodents, the lungs of pocket mice appeared relatively resistant to the toxic effects of oxygen. This conclusion needs, however, to be tempered by the fact that 5% N2 was used in the tests reported here. Nonetheless, the results suggest that the oxygen pressures anticipated on the flight of Apollo XVII should be well tolerated by the pocket mice.
Asunto(s)
Adaptación Fisiológica , Radiación Cósmica , Calor , Pulmón/efectos de los fármacos , Oxígeno/toxicidad , Efectos de la Radiación , Vuelo Espacial , Animales , Ambiente Controlado , Pulmón/patología , Ratones , Microscopía Electrónica , Estados UnidosRESUMEN
A study was made of the eyes of eight pocket mice exposed to oxygen at partial pressures of 8, 10, or 12 psi over a period of 7 d. At the termination of the exposure, the animals were decompressed to sea-level O2 either immediately or over a period of 30, 60, or 90 min. No pathological changes were found in any of the eyes, except in the retina of one of the animals exposed to 12 psi O2. Here, only a single rod photoreceptor was found damaged, an observation not regarded as significant. Hence, an oxygen partial pressure as high as 12 psi in the camister in which pocket mice were expected to fly on Apollo XVII would probably have no deleterious effect on the eyes of the animals.
Asunto(s)
Adaptación Fisiológica , Radiación Cósmica , Ojo/efectos de los fármacos , Calor , Oxígeno/toxicidad , Efectos de la Radiación , Vuelo Espacial , Animales , Cámaras de Exposición Atmosférica , Ambiente Controlado , Ratones , Presión Parcial , Retina/patología , Factores de Tiempo , Estados UnidosRESUMEN
Five pocket mice (Perognathus longimembris) were flown on Apollo XVII, and four survived. All the eyes, except one eye from the dead flight mouse, were examined histologically. In the four surviving mice, a total of five cosmic ray particles which had registered in the subscalp particle detectors had trajectories that intersected the eyes. Four of them (Z equal to 6-9 for three of the particles and Z larger than or equal to 10 for the fourth) most likely went through the head before reaching the particle detector, while the thindown direction of the fifth (Z larger than or equal to 10) was not determinable. The retinas of the flight animals were found free from histological alterations such as might have been expected from encounters with cosmic ray particles.
Asunto(s)
Radiación Cósmica , Ojo/efectos de la radiación , Efectos de la Radiación , Vuelo Espacial , Animales , Ojo/patología , Ratones , Retina/anatomía & histología , Estados UnidosRESUMEN
Histopathological findings in the lungs, livers, bone marrows, small intestines, gonads, kidneys, and other tissues of the four pocket mice (Perognathus longimembris) that survived the Apollo XVII flight were evaluated in the light of their immediate environment and as targest of HZE cosmic ray particles. Results of this study failed to disclose changes that could be ascribed to the HZE particle radiation. Decreased numbers of erythropoietic cells in the bone marrow of the flight mice were probably related to the increased oxygen pressure. The small intestine showed no changes. Ovaries and tests appeared normal. Two of the three surviving male flight mice displayed early stages of spermatogenesis, just as ground-based controls did at the same season. Abnormalities were also not found in the thyroid, parathyroids, adrenals, or kidneys. The status of the juxtaglomerular apparatus could not be evaluated. The lungs exhibited nonspecific slight rections. A variety of incidental lesions were noted in the livers of both the flight mice and their controls. The heart muscle showed nothing that could be regarded as pathological. Sections of skeletal muscle examined were free from significant change.