RESUMEN
The C(17,20)-lyase is a key enzyme in the biosynthesis of androgens by both the testes and adrenals. A complete inhibition of this enzyme would provide an alternative means of androgen suppression for the treatment of prostatic cancers. In the present study, the inhibitory effects of new non-steroidal compounds were tested in vitro on rat C(17,20)-lyase versus abiraterone, a reference steroidal inhibitor. Their activities were also evaluated in vivo on plasma testosterone (T) and luteinizing hormone (LH) levels and on testes, adrenals, seminal vesicles (SV) and ventral prostate (VP) weights after 3 days of oral treatment to adult male rats (50mg/kg per day p.o.). Inhibition in the nanomolar range was obtained with TX 977, the lead racemate product in this series, and optimization is ongoing based on a slight dissociation observed between its two diastereoisomers, TX 1196-11 (S) and TX 1197-11 (R). These non-steroidal compounds (including YM 55208, a reference competitor) proved to be more active in vivo than abiraterone acetate in this model, but the observed impact on adrenal weight suggests that the specificity of lyase inhibition versus corticosteroid biosynthesis deserves further investigations with this new class of potentially useful agents for the treatment of androgen-dependent prostate cancer.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Administración Oral , Androstenos , Androstenoles/farmacología , Animales , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Hormona Luteinizante/sangre , Masculino , Microsomas/enzimología , Tamaño de los Órganos , Ratas , Ratas Wistar , Estereoisomerismo , Testículo/enzimología , Testosterona/sangreRESUMEN
The goal of our research project is to develop a new class of orally active drugs, estrone sulfatase inhibitors, for the treatment of estrogen-dependent (receptor positive) breast cancer. Several compounds were synthesized and their pharmacological potencies explored. Based on encouraging preliminary results, three of them, TX 1299, TX 1492 and TX 1506 were further studied in vitro as well as in vivo. They proved to be strong inhibitors of estrone sulfatase when measured on the whole human JEG-3 choriocarcinoma and MCF-7 breast cancer cells and their IC(50)s found to be in the range of known standard inhibitors. Their residual estrogenic activity was checked as negative in the test of induction of alkaline phosphatase (APase) activity in whole human endometrial adenocarcinoma Ishikawa cells. In addition, their effect on aromatase activity in JEG-3 cells was also examined, since the goal of inhibiting both sulfatase and aromatase activities appears very attractive. However, it has been unsuccessful so far. Then, in vivo potencies of TX 1299, the lead compound in our chemical series, were evaluated in comparison with 6,6,7-COUMATE, a non-steroidal standard, in two different rat models and by oral route. First, the absence of any residual estrogenic activity for these compounds was checked in the uterotrophic model in prepubescent female rats. Second, antiuterotrophic activity in adult ovariectomized rat supplemented with estrone sulfate (E(1)S), showed that both compounds were potent inhibitors, the power of TX 1299 relative to 6,6,7-COUMATE being around 80%. This assay was combined with uterine sulfatase level determination and confirmed the complete inhibition of this enzyme within the target organ. Preliminary studies indicated that other non-steroid compounds in the Théramex series were potent in vitro and in vivo inhibitors of estrone sulfatase in rats and further studies are in progress.
Asunto(s)
Arilsulfatasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Estrógenos/metabolismo , Animales , Aromatasa/metabolismo , Cumarinas/farmacología , Relación Dosis-Respuesta a Droga , Neoplasias Endometriales/metabolismo , Femenino , Humanos , Concentración 50 Inhibidora , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Esteril-Sulfatasa , Sulfatasas/metabolismo , Sulfonamidas/farmacología , Ácidos Sulfónicos , Células Tumorales Cultivadas , Útero/enzimología , Útero/metabolismoRESUMEN
A series of novel, highly potent alpha(v)beta(3) antagonists based on a thiophene scaffold and containing an acylguanidine as an Arg-mimetic is described. A number of structural features, such as cyclic versus open guanidine and a variety of lipophilic side chains, carbamates, sulfonamides and beta-amino acids were explored with respect to inhibition of alpha(v)beta(3) mediated cell adhesion and selectivity versus alpha(IIb)beta(3) binding. In addition, compound 19 was found to be active in the TPTX model of osteoporosis.
Asunto(s)
Osteoporosis/prevención & control , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Receptores de Vitronectina/antagonistas & inhibidores , Animales , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Carbamatos/química , Adhesión Celular/efectos de los fármacos , Adhesión Celular/fisiología , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Guanidina/química , Paratiroidectomía , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/química , Ratas , Receptores de Vitronectina/metabolismo , Sensibilidad y Especificidad , Sulfonamidas/química , Tiofenos/síntesis química , Tiofenos/farmacología , TiroidectomíaRESUMEN
The synthesis of a series of RGD mimetic alpha(v)beta3 antagonists containing a hydantoin scaffold is shown. The results demonstrate some of the structural requirements for the design of selective alpha(v)beta3 antagonists (vs alpha(IIb)beta3) in terms of the Arg-mimetic, the distance between N- and C-terminus and the lipophilic side chain.
Asunto(s)
Hidantoínas/síntesis química , Oligopéptidos/síntesis química , Fibrinógeno/metabolismo , Humanos , Imidazoles/síntesis química , Estructura Molecular , Péptidos/metabolismo , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Unión Proteica/efectos de los fármacos , Receptores de Vitronectina/antagonistas & inhibidoresAsunto(s)
Sistemas de Información en Laboratorio Clínico/organización & administración , Redes de Comunicación de Computadores/organización & administración , Laboratorios de Hospital/organización & administración , Confidencialidad , Documentación , Competencia Económica , Comercialización de los Servicios de Salud , New York , Consultorios Médicos , Técnicas de PlanificaciónRESUMEN
DL-(1-Amino-2-propenyl)phosphonic acid was synthesized through the sequential oxidation, sulfoxide elimination, and deprotection of diphenyl [1-[(benzyloxycarbonyl)amino]-3-(phenylthio)propyl] phosphonate. This analogue of vinylglycine is a strong inhibitor of the alanine racemases from Pseudomonas aeruginosa and Streptococcus faecalis and of the D-Ala:D-Ala ligase from this latter species. This molecule is ineffective against the whole bacterial cells. Unlike vinylglycine, this unsaturated phosphonate does not inhibit the following mammalian enzymes: aspartate aminotransferase, alanine aminotransferase, D-amino acid oxidase, which indicates its specificity. Thus, its incorporation in a peptide structure could induce interesting antimicrobial properties.
Asunto(s)
Alanina Racemasa/antagonistas & inhibidores , Isomerasas de Aminoácido/antagonistas & inhibidores , Antibacterianos/farmacología , Compuestos Organofosforados/farmacología , Alanina Transaminasa/antagonistas & inhibidores , Antibacterianos/síntesis química , Aspartato Aminotransferasas/antagonistas & inhibidores , Bacterias/efectos de los fármacos , D-Aminoácido Oxidasa/antagonistas & inhibidores , Compuestos Organofosforados/síntesis química , Péptido Sintasas/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The (beta-chloro-, (beta, beta-dichloro-, and (beta, beta, beta-trichloro-alpha-aminoethyl)phosphonic acids have been synthesized and their inhibitory properties on the alanine racemases [EC 5.1.1.1] and the D-Ala:D-Ala ligases [EC 6.3.2.4] from Pseudomonas aeruginosa and Streptococcus faecalis have been evaluated. The monochloro and the dichloro derivatives of Ala-P exhibit a strong inhibition on the racemases of the two species tested but do not behave as suicide substrates. Only the D-Ala:D-Ala ligase of S. faecalis is inhibited by these compounds. The poor antibacterial activity observed with beta-chloro- and beta, beta-dichloro-Ala-P might be enhanced by the peptide-transport strategy.