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1.
Bioorg Med Chem Lett ; 23(4): 1120-6, 2013 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-23298810

RESUMEN

Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors.


Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Benzoxazoles/síntesis química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Humanos , Oxidorreductasas Intramoleculares/química , Oxidorreductasas Intramoleculares/metabolismo , Modelos Moleculares , Conformación Molecular , Prostaglandina-E Sintasas , Relación Estructura-Actividad
2.
Bioorg Med Chem ; 15(10): 3390-412, 2007 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-17387018

RESUMEN

The integrin alpha(v)beta(3) is expressed in a number of cell types and is thought to play a major role in several pathological conditions. Various small molecules that inhibit the integrin have been shown to suppress tumor growth and retinal angiogenesis. The tripeptide Arg-Gly-Asp (RGD), a common binding motif in several ligands that bind to alpha(v)beta(3), has been depeptidized and optimized in our efforts toward discovering a small molecule inhibitor. We recently disclosed the synthesis and biological activity of several small molecules that did not contain any peptide bond and mimic the tripeptide RGD. The phenethyl group in one of the lead compounds was successfully replaced with a cyclopropyl moiety. The new lead compound was optimized for potency, selectivity, and for its ADME properties. We describe herein the discovery, synthesis, and optimization of cyclopropyl containing analogs that are potent and selective inhibitors of alpha(v)beta(3).


Asunto(s)
Acetatos/síntesis química , Acetatos/farmacología , Integrina alfaVbeta3/antagonistas & inhibidores , Naftiridinas/síntesis química , Naftiridinas/farmacología , Animales , Área Bajo la Curva , Línea Celular , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Diseño de Fármacos , Semivida , Humanos , Indicadores y Reactivos , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Espectrofotometría Ultravioleta , Relación Estructura-Actividad , Transfección
3.
Bioorg Med Chem ; 15(11): 3783-800, 2007 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-17399986

RESUMEN

The integrin alpha(v)beta(3), vitronectin receptor, is expressed in a number of cell types and has been shown to mediate adhesion of osteoclasts to bone matrix, vascular smooth muscle cell migration, and angiogenesis. We recently disclosed the discovery of a tripeptide Arg-Gly-Asp (RGD) mimic, which has been shown to be a potent inhibitor of the integrin alpha(v)beta(3) and has excellent anti-angiogenic properties including its suppression of tumor growth in animal models. In other investigations involving RGD mimics, only compounds containing the S-isomers of the beta-amino acids have been shown to be potent. We were surprised to find the potencies of analogs containing enantiomerically pure S-isomers of beta-amino acids which were only marginally better than the corresponding racemic mixtures. We therefore synthesized RGD mimics containing R-isomers of beta-amino acids and found them to be relatively potent inhibitors of alpha(v)beta(3). One of the compounds was examined in tumor models in mice and has been shown to significantly reduce the rate of growth and the size of tumors.


Asunto(s)
Aminoácidos/química , Antineoplásicos/química , Antineoplásicos/farmacología , Integrina alfaVbeta3/antagonistas & inhibidores , Imitación Molecular , Oligopéptidos/química , Oligopéptidos/farmacología , Aminoácidos/síntesis química , Animales , Antineoplásicos/farmacocinética , Neoplasias del Colon , Hipercalcemia/inducido químicamente , Isomerismo , Melanoma , Ratones , Ratones Endogámicos , Oligopéptidos/farmacocinética , Neoplasias Cutáneas , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Bioorg Med Chem ; 11(22): 4769-77, 2003 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-14556792

RESUMEN

The human immunodeficiency virus (HIV) has been shown to be the causative agent for AIDS. The HIV virus encodes for a unique aspartyl protease that is essential for the production of enzymes and proteins in the final stages of maturation. Protease inhibitors have been useful in combating the disease. The inhibitors incorporate a variety of isosteres including the hydroxyethylurea at the protease cleavage site. We have shown that the replacement of t-butylurea moiety by benzothiazolesulfonamide provided inhibitors with improved potency and antiviral activities. Some of the compounds have shown good oral bioavailability and half-life in rats. The synthesis of benzothiazole derivatives led us to explore other heterocycles. During the course of our studies, we also developed an efficient synthesis of benzothiazole-6-sulfonic acid via a two-step procedure starting from sulfanilamide.


Asunto(s)
Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología , Tiazoles/química , Tiazoles/farmacología , Urea/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Concentración 50 Inhibidora , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Tiazoles/síntesis química , Tiazoles/farmacocinética , Urea/química , Urea/farmacología
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