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1.
Regul Toxicol Pharmacol ; 127: 105074, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34757112

RESUMEN

The Threshold of Toxicological Concern (TTC) for non-genotoxic substances, a risk assessment tool to establish safe exposure levels for chemicals with insufficient toxicological data, is based on the 5th percentile of cumulated distributions of Point of Departures in a high amount of repeat-dose, developmental and reproductive toxicity studies, grouped by Cramer Classes. The lack of organosilicon compounds in this dataset has resulted in regulatory concerns over the applicability of the TTC concept for this chemistry. We collected publicly available, scientifically robust oral repeat-dose and DART studies for 71 organosilicon substances for inclusion in the existing TTC dataset, using criteria for evaluation of studies and derivation of points of departure analogous to the Munro and COSMOS TTC publications. The resulting 5th percentile of this dataset was 13-fold higher than the 5th percentile for Cramer Class III compounds reported by Munro (which is the default for silicon-containing substances). Both the existing TTC for Cramer Class III compounds from Munro (1.5 µg/kg bw/day) and the COSMOS TTC (2.3 µg/kg bw/day), recommended by the SCCS for cosmetics-related substances, provide a conservative and sufficiently protective approach for this class of chemistry.


Asunto(s)
Compuestos de Organosilicio/farmacología , Reproducción/efectos de los fármacos , Animales , Pruebas de Carcinogenicidad , Cosméticos/farmacología , Cosméticos/toxicidad , Bases de Datos Factuales , Relación Dosis-Respuesta a Droga , Pruebas de Mutagenicidad , Nivel sin Efectos Adversos Observados , Compuestos de Organosilicio/toxicidad , Plaguicidas/farmacología , Plaguicidas/toxicidad , Conejos , Roedores
2.
Regul Toxicol Pharmacol ; 62(1): 160-82, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22019814

RESUMEN

In the absence of toxicological data on a chemical, the threshold of toxicological concern (TTC) approach provides a system to estimate a conservative exposure below which there is a low probability of risk for adverse health effects. The original toxicology dataset underlying the TTC was based on NOELs from repeat dose studies. Subsequently there have been several efforts to assess whether or not these limits are also protective for reproductive/developmental effects. This work expands the database of chemicals with reproductive and developmental data, presents these data in a comprehensive and transparent format and groups the chemicals according to the TTC "Cramer Class" rules. Distributions of NOAELs from each of these classes were used to assess whether the previously proposed TTC values based on repeat dose data are protective for reproductive/developmental toxicity endpoints as well. The present analysis indicates that, for each Cramer Class, the reproductive and developmental endpoints would be protected at the corresponding general TTC tiers derived by Munro et al. (1996).


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Desarrollo Embrionario/efectos de los fármacos , Desarrollo Fetal/efectos de los fármacos , Sustancias Peligrosas/toxicidad , Reproducción/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Humanos , Nivel sin Efectos Adversos Observados , Medición de Riesgo , Pruebas de Toxicidad
3.
Bioorg Med Chem ; 15(3): 1311-22, 2007 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-17127070

RESUMEN

Peptidomimetic compounds possessing a caprolactam ring constraint were prepared and evaluated as interleukin-1beta converting enzyme (ICE) inhibitors. The caprolactam ring was used to constrain the P3 region of our inhibitors. This strategy proved to be effective for the synthesis of ICE inhibitors, maintaining key hydrogen bond interactions with the enzyme and invoking a preferred conformation for binding. Several compounds exhibited IC(50) values less than 10nM in a caspase-1 enzyme assay and less than 100nM in a THP-1 whole cell assay measuring IL-1beta production. Two compounds, 13c and 13j, were found to have good oral bioavailability (>50%) in rats when administered as prodrugs.


Asunto(s)
Caprolactama/síntesis química , Inhibidores de Caspasas , Inhibidores Enzimáticos/farmacología , Serpinas/síntesis química , Proteínas Virales/síntesis química , Animales , Disponibilidad Biológica , Caprolactama/química , Caprolactama/farmacología , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Interleucina-1beta/metabolismo , Masculino , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Serpinas/farmacología , Relación Estructura-Actividad , Proteínas Virales/farmacología
4.
Bioorg Med Chem Lett ; 16(21): 5659-63, 2006 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-16919947

RESUMEN

The synthesis and structure-activity relationships of a novel series of N-sulfonyl-2-indole carboxamides that bind to peroxisome proliferator-activated receptor gamma (PPAR-gamma) are reported. Chemical optimization of the series led to the identification of 4q (IC(50)=50 nM) as a potent binding agent of PPAR-gamma. Also reported is preliminary cell based data suggesting the use of these compounds in the treatment of osteoporosis.


Asunto(s)
Amidas/farmacología , Diseño de Fármacos , Indoles/farmacología , Osteoporosis/tratamiento farmacológico , PPAR gamma/metabolismo , Células 3T3 , Amidas/síntesis química , Animales , Indoles/síntesis química , Ratones
5.
Bioorg Med Chem Lett ; 16(18): 4728-32, 2006 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-16870441

RESUMEN

A series of monocyclic thiazepine inhibitors of interleukin-1beta converting enzyme (ICE) were synthesized in eight steps from commercially available intermediates. In vitro biological evaluation showed the thiazepines to be moderately potent ICE inhibitors, with the most active compound exhibiting an IC50 value of 30 nM in an enzyme inhibition assay. Compounds of this class possessed good selectivity against the related enzymes caspase-3 and caspase-8.


Asunto(s)
Inhibidores de Caspasas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Tiazepinas/síntesis química , Tiazepinas/farmacología , Caspasa 1/metabolismo , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tiazepinas/química
6.
Bioorg Med Chem Lett ; 16(16): 4233-6, 2006 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-16782334

RESUMEN

Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).


Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Aminoimidazol Carboxamida/síntesis química , Inhibidores de Caspasas , Hidrazinas/síntesis química , Hidrazinas/farmacología , Aminoimidazol Carboxamida/análogos & derivados , Caspasa 8 , Química Farmacéutica/métodos , Cisteína Endopeptidasas/metabolismo , Industria Farmacéutica/métodos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Químicos
7.
Bioorg Med Chem ; 14(23): 7880-92, 2006 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-16908171

RESUMEN

An 8,5-fused bicyclic peptidomimetic ring system generated by a stereoselective ring metathesis reaction was elaborated into potent inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1). Multiple compounds were found that exhibited ICE IC50 values < 10 nM and were selective over caspase-3 and caspase-8. These active analogs generally possessed good activity (IC50 values < 100 nM) in a whole cell assay measuring IL-1beta production. Pharmacokinetic analysis of the ethyl acetal prodrug form of a selected active lead revealed a compound with a reasonable plasma half-life (1.1 h) and good oral bioavailability (30%).


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores de Caspasas , Péptidos Cíclicos/farmacología , Animales , Disponibilidad Biológica , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Semivida , Concentración 50 Inhibidora , Imitación Molecular , Péptidos Cíclicos/síntesis química , Profármacos/farmacocinética , Relación Estructura-Actividad , Especificidad por Sustrato
8.
Bioorg Med Chem Lett ; 15(19): 4322-6, 2005 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-16046129

RESUMEN

The application of a tricyclic pyrrolopyrimidinone scaffold for the synthesis of peptidomimetic inhibitors of interleukin-1beta-converting enzyme (ICE) is reported. The synthesis of the tricyclic scaffold and conversion of it to a variety of target ICE inhibitors were accomplished in 4-5 steps. In vitro biological evaluation of the tricyclic pyrrolopyrimidinones revealed fair to good ICE inhibitors, with the most active compound exhibiting an IC50 of 14 nM in a caspase-1 enzyme binding assay.


Asunto(s)
Inhibidores de Caspasas , Dipéptidos/síntesis química , Pirimidinonas/síntesis química , Dipéptidos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Factores Inmunológicos/síntesis química , Factores Inmunológicos/farmacología , Concentración 50 Inhibidora , Imitación Molecular , Monocitos , Pirimidinonas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 15(19): 4291-4, 2005 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-16046125

RESUMEN

A novel diazocan containing dipeptide mimetic was synthesized via reductive N-N bond cleavage of a pyrazolidino-pyrazolidine using Raney-Ni and evaluated as an ICE inhibitor. This versatile 8-membered ring containing scaffold possesses an N-5 ring nitrogen that was used to explore structure-activity relationships in a cell-based assay measuring inhibition of interleukin-1beta.


Asunto(s)
Dipéptidos/síntesis química , Interleucina-1/antagonistas & inhibidores , Péptidos Cíclicos/síntesis química , Inhibidores de Caspasas , Dipéptidos/química , Dipéptidos/farmacología , Evaluación Preclínica de Medicamentos , Concentración 50 Inhibidora , Interleucina-1/biosíntesis , Conformación Molecular , Imitación Molecular , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Pirazoles/química , Relación Estructura-Actividad
10.
Bioorg Med Chem Lett ; 15(24): 5434-8, 2005 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-16216507

RESUMEN

Two novel 8,6-fused bicyclic peptidomimetic ring systems were synthesized utilizing olefin metathesis as the key reaction for the formation of the eight-membered ring. Both peptidomimetic scaffolds were further elaborated into potent ICE inhibitors, with numerous compounds exhibiting caspase-1 IC(50)s less than 10nM.


Asunto(s)
Biomimética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores de Caspasas , Inhibidores Enzimáticos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Inhibidores Enzimáticos/síntesis química , Humanos , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular
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