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1.
Bioorg Med Chem Lett ; 25(22): 5040-7, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26497283

RESUMO

The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Guanidinas/farmacologia , Compostos Macrocíclicos/farmacologia , Prolina/análogos & derivados , Prolina/farmacologia , Inibidores de Proteases/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Peptídeos beta-Amiloides/biossíntese , Animais , Células CACO-2 , Catepsina D/antagonistas & inibidores , Catepsina E/antagonistas & inibidores , Cães , Guanidinas/síntese química , Humanos , Compostos Macrocíclicos/síntese química , Células Madin Darby de Rim Canino , Masculino , Camundongos , Simulação de Acoplamento Molecular , Pepsina A/antagonistas & inibidores , Prolina/síntese química , Inibidores de Proteases/síntese química
2.
J Med Chem ; 55(21): 9208-23, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-23030502

RESUMO

This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Aß levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Aß levels were not obtained.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Guanidinas/síntese química , Bibliotecas de Moléculas Pequenas , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/química , Encéfalo/metabolismo , Linhagem Celular , Cristalografia por Raios X , Guanidinas/farmacocinética , Guanidinas/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Modelos Moleculares , Estrutura Molecular , Mutação , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Ensaio Radioligante , Ratos , Técnicas de Síntese em Fase Sólida , Soluções , Relação Estrutura-Atividade
3.
J Med Chem ; 54(19): 6548-62, 2011 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-21882820

RESUMO

Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine residues, a process that involves a conserved tryptophan-proline-aspartate (WPD) loop in catalysis. In previously determined structures of PTPs, the WPD-loop has been observed in either an "open" conformation or a "closed" conformation. In the current work, X-ray structures of the catalytic domain of receptor-like protein tyrosine phosphatase γ (RPTPγ) revealed a ligand-induced "superopen" conformation not previously reported for PTPs. In the superopen conformation, the ligand acts as an apparent competitive inhibitor and binds in a small hydrophobic pocket adjacent to, but distinct from, the active site. In the open and closed WPD-loop conformations of RPTPγ, the side chain of Trp1026 partially occupies this pocket. In the superopen conformation, Trp1026 is displaced allowing a 3,4-dichlorobenzyl substituent to occupy this site. The bound ligand prevents closure of the WPD-loop over the active site and disrupts the catalytic cycle of the enzyme.


Assuntos
Modelos Moleculares , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/antagonistas & inibidores , Tiofenos/química , Sequência de Aminoácidos , Domínio Catalítico , Cristalografia por Raios X , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Dados de Sequência Molecular , Ligação Proteica , Conformação Proteica , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/química , Relação Estrutura-Atividade , Tiofenos/síntese química
4.
Proc Natl Acad Sci U S A ; 108(37): 15366-71, 2011 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-21896751

RESUMO

Influenza nucleoprotein (NP) plays multiple roles in the virus life cycle, including an essential function in viral replication as an integral component of the ribonucleoprotein complex, associating with viral RNA and polymerase within the viral core. The multifunctional nature of NP makes it an attractive target for antiviral intervention, and inhibitors targeting this protein have recently been reported. In a parallel effort, we discovered a structurally similar series of influenza replication inhibitors and show that they interfere with NP-dependent processes via formation of higher-order NP oligomers. Support for this unique mechanism is provided by site-directed mutagenesis studies, biophysical characterization of the oligomeric ligand:NP complex, and an X-ray cocrystal structure of an NP dimer of trimers (or hexamer) comprising three NP_A:NP_B dimeric subunits. Each NP_A:NP_B dimeric subunit contains two ligands that bridge two composite, protein-spanning binding sites in an antiparallel orientation to form a stable quaternary complex. Optimization of the initial screening hit produced an analog that protects mice from influenza-induced weight loss and mortality by reducing viral titers to undetectable levels throughout the course of treatment.


Assuntos
Antivirais/farmacologia , Nucleoproteínas/química , Nucleoproteínas/metabolismo , Orthomyxoviridae/fisiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Cristalografia por Raios X , Modelos Animais de Doenças , Ensaios de Triagem em Larga Escala , Hidrodinâmica , Camundongos , Modelos Moleculares , Nucleoproteínas/ultraestrutura , Orthomyxoviridae/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Bibliotecas de Moléculas Pequenas/uso terapêutico , Soluções
5.
PLoS Pathog ; 6(9): e1001086, 2010 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-20838466

RESUMO

Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 µM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/metabolismo , Internalização do Vírus/efeitos dos fármacos , Sequência de Aminoácidos , Antígenos CD/genética , Antígenos CD/metabolismo , Antivirais/isolamento & purificação , Células Cultivadas , Farmacorresistência Viral , Sinergismo Farmacológico , Hepacivirus/isolamento & purificação , Hepacivirus/metabolismo , Hepatite C/genética , Hepatite C/virologia , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Interferons/uso terapêutico , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Bibliotecas de Moléculas Pequenas/análise , Tetraspanina 28 , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo
6.
Bioorg Med Chem Lett ; 18(18): 5083-6, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18722770

RESUMO

The discovery and optimization of a novel series of prolinol-derived GHSR agonists is described. This series emerged from a 11,520-member solid-phase library targeting the GPCR protein superfamily, and the rapid optimization of low micromolar hits into single-digit nanomolar leads can be attributed to the solid-phase synthesis of matrix libraries, which revealed multiple non-additive structure-activity relationships. In addition, the separation of potent diastereomers highlighted the influence of the alpha-methyl stereochemistry of the phenoxyacetamide sidechain on GHSR activity.


Assuntos
Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores de Grelina/agonistas , Técnicas de Química Combinatória , Estrutura Molecular , Pirrolidinas/química , Estereoisomerismo , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 13(17): 2883-5, 2003 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-14611849

RESUMO

The synthesis of novel ligands for the NPY(2) receptor using solid phase split pool methodology is described. One of the analogues, diamine 16, was found to be a potent NPY(2) binder.


Assuntos
Diaminas/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Acilação , Linhagem Celular Tumoral , Diaminas/síntese química , Humanos , Concentração Inibidora 50 , Ligantes , Neuroblastoma/metabolismo , Ensaio Radioligante , Relação Estrutura-Atividade
8.
Peptides ; 23(8): 1485-90, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12182951

RESUMO

The actions of neuropeptide Y (NPY) are mediated by at least six G-protein coupled receptors denoted as Y(1), Y(2), Y(3), Y(4), Y(5), and y(6). Investigations using receptor selective ligands and receptor knock-out mice suggest that NPY effects on feeding are mediated by both Y(1) and Y(5) receptors. We have previously shown that Cys-dimers of NPY C-terminal peptides exhibit Y(1) selectivity relative to Y(2) receptors. Re-investigation of their selectivity with respect to the newly cloned receptors, has identified bis(31/31') [[Cys(31), Nva(34)]NPY(27-36)-NH(2)] (BWX-46) as a Y(5) receptor selective agonist. BWX-46 selectively bound Y(5) receptors, and inhibited cAMP synthesis by Y(5) cells with potencies comparable to that of NPY. Moreover, BWX-46 (10 microM) exhibited no significant effect on the cAMP synthesis by Y(1), Y(2), and Y(4) cells. Thus, BWX-46 constitutes the lowest molecular weight Y(5) selective agonist reported to date. Intrahypothalamic (i.h.t)-injection of 30 and 40 microg of BWX-46 stimulated the food intake by rats in a gradual manner, reaching maximal level 8 h after injection. This response was similar to that exhibited by other Y(5) selective agonists, but differed from that of NPY, which exhibited a rapid orexigenic stimulus within 1 h. It is suggested that the differences in the orexigenic stimuli of NPY and Y(5) agonists may be due to their differences in the signal transduction mechanisms.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptores de Neuropeptídeo Y/agonistas , Animais , Membrana Celular/metabolismo , Masculino , Neuropeptídeo Y/análogos & derivados , Neuropeptídeo Y/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/metabolismo
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