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

RESUMO

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.


Assuntos
Benzoxazóis/química , Benzoxazóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Benzoxazóis/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Oxirredutases Intramoleculares/química , Oxirredutases Intramoleculares/metabolismo , Modelos Moleculares , Conformação Molecular , Prostaglandina-E Sintases , Relação Estrutura-Atividade
2.
Bioorg Med Chem ; 15(10): 3390-412, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17387018

RESUMO

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).


Assuntos
Acetatos/síntese química , Acetatos/farmacologia , Integrina alfaVbeta3/antagonistas & inibidores , Naftiridinas/síntese química , Naftiridinas/farmacologia , Animais , Área Sob a Curva , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Desenho de Fármacos , Meia-Vida , Humanos , Indicadores e Reagentes , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , Transfecção
3.
Bioorg Med Chem ; 15(11): 3783-800, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17399986

RESUMO

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.


Assuntos
Aminoácidos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Integrina alfaVbeta3/antagonistas & inibidores , Mimetismo Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Aminoácidos/síntese química , Animais , Antineoplásicos/farmacocinética , Neoplasias do Colo , Hipercalcemia/induzido quimicamente , Isomerismo , Melanoma , Camundongos , Camundongos Endogâmicos , Oligopeptídeos/farmacocinética , Neoplasias Cutâneas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Bioorg Med Chem ; 11(22): 4769-77, 2003 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-14556792

RESUMO

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.


Assuntos
Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Ureia/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacocinética , Humanos , Concentração Inibidora 50 , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Tiazóis/síntese química , Tiazóis/farmacocinética , Ureia/química , Ureia/farmacologia
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