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1.
Bioorg Med Chem Lett ; 30(16): 127299, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32631519

RESUMO

Inducing oligodendrocyte progenitor cell (OPC) differentiation is a novel therapeutic strategy for the treatment of demyelinating diseases such as multiple sclerosis (MS). In the preceding article, we detailed the discovery of compound 1, a potent inducer of OPC differentiation possessing a characteristic spiroindoline structure. Also, we found that N-methylation and des-carbonyl compound 1 (4) led to a loss in potency. Herein, we describe our investigations of a conformation-based hypothesis for OPC differentiation activity based on the preferred conformation of the spiro core, and further structure-activity relationship (SAR) exploration led to the identification of 6-CF3 derivative 8, which was more potent compared to compound 1.


Assuntos
Desenho de Fármacos , Indóis/farmacologia , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Diferenciação Celular , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Estrutura Molecular , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 29(11): 1419-1422, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30952590

RESUMO

A novel series of benzothiophene derivatives was discovered as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity relationship studies on high-throughput screening hit compound 1 led to the identification of 7-acetyl-3-methyl-N-(quinolin-2-yl)-1-benzothiophene-2-carboxamide (16), with potent inhibitory activity (PDE10A IC50 = 7.6 nM) and selectivity (>1300-fold selectivity over the other tested phosphodiesterases). In addition, a novel methyl-induced conformational alteration of the benzothiophene-2-carboxamide derivatives is reported.


Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Tiofenos/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
3.
Bioorg Med Chem Lett ; 29(2): 334-338, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30522951

RESUMO

A series of imidazolinylindole derivatives were discovered as novel kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Structure-activity relationship (SAR) studies led to the identification of potent human KLK7 inhibitors. By further modification of the benzenesulfonyl moiety to overcome species differences in inhibitory activity, potent inhibitors against both human and mouse KLK7 were identified. Furthermore, the complex structure of 25 with mouse KLK7 could explain the SAR and the cause of the species differences in inhibitory activity.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Imidazolinas/farmacologia , Indóis/farmacologia , Calicreínas/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Imidazolinas/síntese química , Imidazolinas/química , Indóis/síntese química , Indóis/química , Calicreínas/metabolismo , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
4.
Bioorg Med Chem ; 26(12): 3639-3653, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29884582

RESUMO

A series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were prepared as kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Previously reported compounds 1-3 were potent human KLK7 inhibitors; however, they did not exhibit inhibitory activity against mouse KLK7. Comparison of the human and mouse KLK7 structures reveals the cause of this species differences; therefore, compounds that could inhibit both KLK7s were designed, synthesized, and evaluated. Through this structure-based drug design, compound 22g was identified as an inhibitor against human and mouse KLK7, and only one of the enantiomers, (-)-22g, exhibited potent inhibitory activity. Furthermore, the crystal structure of mouse KLK7 complexed with 22g enabled the elucidation of structure-activity relationships and justified 22g as a valuable compound to overcome the species differences.


Assuntos
Azepinas/química , Calicreínas/metabolismo , Inibidores de Proteases/síntese química , Sequência de Aminoácidos , Animais , Azepinas/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Calicreínas/antagonistas & inibidores , Camundongos , Inibidores de Proteases/metabolismo , Estrutura Terciária de Proteína , Alinhamento de Sequência , Especificidade da Espécie , Estereoisomerismo , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 28(8): 1371-1375, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29550094

RESUMO

A novel series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were investigated as human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Based on the X-ray co-crystal structure of compound 1 bound to human KLK7, the derivatives of this scaffold were designed, synthesized, and evaluated. Through structure-activity relationship studies focused on the side chain located in the prime site region of the enzyme, representative compounds 15, 33a, and 35a were identified as highly potent and selective inhibitors of human KLK7.


Assuntos
Azepinas/farmacologia , Calicreínas/antagonistas & inibidores , Azepinas/síntese química , Azepinas/química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Calicreínas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 28(2): 188-192, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29191554

RESUMO

Based on insight from the X-ray crystal structure of human chymase in complex with compound 1, a lactam carbonyl of the diazepane core was exchanged with O-substituted oxyimino group, leading to amidoxime derivatives. This modification resulted in highly potent chymase inhibitors, such as O-phenylamidoxime 5f. X-ray crystal structure analysis indicated that compound 5f induced movement of the Leu99 and Tyr94 side chains at the S2 site, and the increase in inhibitory activity of O-phenyl amidoxime derivatives suggested that the O-phenyl moiety interacted with the Tyr94 residue. Surface plasmon resonance experiments showed that compound 5f had slower association and dissociation kinetics and the calculated residence time of compound 5f to human chymase was extended compared to that of amide compound 1.


Assuntos
Quimases/antagonistas & inibidores , Desenho de Fármacos , Oximas/farmacologia , Inibidores de Serina Proteinase/farmacologia , Sítios de Ligação/efeitos dos fármacos , Quimases/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Oximas/síntese química , Oximas/química , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade
7.
Bioorg Med Chem ; 25(24): 6680-6694, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29153628

RESUMO

Natriuretic peptide receptor A (NPR-A) agonists were evaluated in vivo by optimizing the structure of quinazoline derivatives to improve agonistic activity for rat NPR-A. A 1,4-Cis-aminocyclohexylurea moiety at 4-position and hydroxy group of d-alaninol at 2-position on the quinazoline ring were found to be important factors in improving rat NPR-A activity. We identified potent quinazoline and pyrido[2,3-d]pyrimidine derivatives against rat NPR-A, with double-digit nanomolar EC50 values. The in vivo results showed that compound 56b administered at 1.0 mg/kg/min significantly increased plasma cGMP concentration and urine volume in rats. We discovered novel potent NPR-A agonists that showed agonistic effects similar to those of atrial natriuretic peptide.


Assuntos
Descoberta de Drogas , Quinazolinas/farmacologia , Receptores do Fator Natriurético Atrial/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 27(21): 4904-4907, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28958620

RESUMO

Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48, which showed potent agonistic activity for NPR-A with an EC50 value of 0.073µM, indicating 350-fold potency compared to the hit compound 3.


Assuntos
Pirimidinas/metabolismo , Receptores do Fator Natriurético Atrial/agonistas , Animais , Células CHO , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Humanos , Pirimidinas/síntese química , Pirimidinas/química , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/metabolismo , Receptores do Fator Natriurético Atrial/metabolismo , Relação Estrutura-Atividade
9.
Bioorg Med Chem ; 25(6): 1762-1769, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28190653

RESUMO

Novel agonists of the Natriuretic Peptide Receptor A (NPR-A) were obtained through random screening and subsequent structural modification of triazine derivatives. The key structural feature to improve in vitro activity was the dimerization of triazine monomer derivatives. The non peptide derivative 7c and 13a showed highly potent NPR-A agonistic activity in vitro and diuretic activity in vivo. These results implied that non-peptidic small molecules open the possibility of new therapy for congestive heart failure.


Assuntos
Descoberta de Drogas , Receptores do Fator Natriurético Atrial/agonistas , Triazinas/farmacologia , Animais , Cristalografia por Raios X , GMP Cíclico/metabolismo , Dimerização , Diuréticos/farmacologia , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Espectrometria de Massas/métodos , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazinas/química
10.
Biochem Biophys Res Commun ; 381(4): 654-9, 2009 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-19250926

RESUMO

Bone marrow- (BM-) derived cells can differentiate into smooth muscle-like cells (SMLC), resulting in vascular pathogenesis. However, the molecular mechanism of the differentiation remains unknown. We have recently reported that Notch signaling promotes while a Notch target HERP1 inhibit the differentiation of mesenchymal cells to SMC. During the differentiation of BM-derived mononuclear cells into smooth muscle alpha-actin (SMA)-positive cells, expression of Jagged1 and SMC-specific Notch3 was increased. Blocking Notch with gamma-secretase inhibitor prevented the induction of SMA. Wire-mediated vascular injury was produced in femoral arteries in mice transplanted with green fluorescent protein (GFP)-positive cells. Many double-positive cells for GFP/Jagged1 or GFP/Notch3 were detected in the thickened neointima. In contrast, only a few SMA-positive cells were positive for GFP in neointima where HERP1, a suppressor for Notch, were abundantly expressed. In conclusion, Notch-HERP1 pathway plays an important role in differentiation of BM-derived mononuclear cells into SMLC.


Assuntos
Artérias/lesões , Artérias/patologia , Células da Medula Óssea/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Notch/metabolismo , Animais , Artérias/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Células da Medula Óssea/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Diferenciação Celular , Células Cultivadas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína Jagged-1 , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptor Notch3 , Receptor Notch4 , Proteínas Repressoras/biossíntese , Proteínas Serrate-Jagged , Transdução de Sinais , Túnica Íntima/lesões , Túnica Íntima/metabolismo , Túnica Íntima/patologia
11.
Biochemistry ; 44(33): 11115-21, 2005 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-16101295

RESUMO

The AcrAB-TolC system exports a wide variety of drugs and toxic compounds, and confers intrinsic drug tolerance on Escherichia coli. The crystal structures suggested that AcrB and TolC directly dock with each other. However, biochemical and biophysical evidence of their interaction has been contradictory until recently. In this study, we examine the interaction sites by means of in vivo disulfide cross-linking between cysteine residues introduced by site-directed mutagenesis at the tops of the vertical hairpins of AcrB and the bottoms of the coiled coils of polyhistidine-tagged TolC molecules, which are structurally predicted docking sites. The AcrB-TolC complex formed through disulfide cross-linking was detected when a specific pair of mutants was coexpressed in E. coli. Our observations suggested that the AcrB-TolC complex may be formed through a two-step mechanism via transient tip-to-tip interaction of AcrB and TolC. The cross-linking was not affected by AcrA, the substrate, or a putative proton coupling site mutation.


Assuntos
Proteínas da Membrana Bacteriana Externa/química , Proteínas de Transporte/química , Dissulfetos/química , Proteínas de Escherichia coli/química , Escherichia coli/química , Proteínas de Membrana/química , Complexos Multiproteicos/química , Substituição de Aminoácidos/genética , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Membrana Celular/genética , Membrana Celular/metabolismo , Cisteína/química , Cisteína/genética , Cisteína/metabolismo , Dissulfetos/metabolismo , Tolerância a Medicamentos/fisiologia , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Expressão Gênica , Histidina/química , Histidina/genética , Histidina/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Mutação Puntual , Ligação Proteica/genética , Estrutura Quaternária de Proteína/genética , Estrutura Secundária de Proteína/genética
12.
Chembiochem ; 5(3): 298-310, 2004 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-14997522

RESUMO

Model building of the two photointermediates, lumirhodopsin and metarhodopsin I, and the activated form of rhodopsin, metarhodopsin II, is described. An outward swing of the C-terminal portion of transmembrane segment 3, pivoting on Cys110 at the N-terminal end of transmembrane segment 3, led to structural models of lumirhodopsin and metarhodopsin I. The conformation of the chromophore in the lumirhodopsin and metarhodopsin I models is controlled by the motion of transmembrane segment 3 and agreed closely with the hydrogen-bonding states of the protonated Schiff base in lumirhodopsin and metarhodopsin I as deduced from their FTIR and resonance Raman spectra and with the negative and positive CD bands of lumirhodopsin and metarhodopsin I, respectively. The structure of metarhodopsin II was constructed by an outward swing of transmembrane segment 3 and the rigid-body motion of transmembrane segment 6. The arrangement of the entire transmembrane segment of the metarhodopsin II model closely agreed with the electron paramagnetic resonance spectra of spin-labeled rhodopsin mutants and provided a structural basis for the protonation of Glu134, which is a key process in transducin activation.


Assuntos
Modelos Moleculares , Rodopsina/análogos & derivados , Rodopsina/química , Animais , Humanos , Ligação de Hidrogênio , Estrutura Molecular , Movimento (Física) , Fotoquímica , Conformação Proteica , Bases de Schiff
14.
Biochem J ; 371(Pt 1): 175-81, 2003 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-12513696

RESUMO

13C-NMR spectroscopy was used to estimate the p K a values for the Tyr(150) (Y150) residue in wild-type and mutant class C beta-lactamases. The tyrosine residues of the wild-type and mutant lactamases were replaced with (13)C-labelled L-tyrosine ([ phenol -4-(13)C]tyrosine) in order to observe the tyrosine residues selectively. Spectra of the wild-type and K67C mutant (Lys(67)-->Cys) enzyme were compared with the Y150C mutant lactamase spectra to identify the signal originating from Tyr(150). Titration experiments showed that the chemical shift of the Tyr(150) resonance in the wild-type enzyme is almost invariant in a range of 0.1 p.p.m. up to pH 11 and showed that the p K (a) of this residue is well above 11 in the substrate-free form. According to solvent accessibility calculations on X-ray-derived structures, the phenolic oxygen of Tyr(150), which is near the amino groups of Lys(315) and Lys(67), appears to have low solvent accessibility. These results suggest that, in the native enzyme, Tyr(150) in class C beta-lactamase of Citrobacter freundii GN346 is protonated and that when Tyr(150) loses a proton, a proton from Lys(67) would replace it. Consequently, Tyr(150) would be protonated during the entire titration.


Assuntos
Citrobacter freundii/enzimologia , Tirosina/química , beta-Lactamases/química , Sequência de Aminoácidos , Sítios de Ligação , Concentração de Íons de Hidrogênio , Lisina , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Fragmentos de Peptídeos/análise , Mutação Puntual , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Titulometria , beta-Lactamases/classificação , beta-Lactamases/genética
15.
Bioorg Med Chem Lett ; 12(9): 1245-7, 2002 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-11965363

RESUMO

MiniANP is a synthetic pentadecapeptide analogue of atrial natriuretic polypeptide (ANP). We have used the proline-scanning mutagenesis and the analogue peptides with shorter backbones to characterize the turn-like conformation at residue 6-9 and an extended structure of Gly5-Gly6 as the receptor-bound structure of miniANP. A docking study of miniANP at the binding site of the type A natriuretic peptide receptor (NPR-A) supported the deduced conformation in the receptor-bound structure.


Assuntos
Fator Natriurético Atrial/química , Fator Natriurético Atrial/farmacologia , Prolina/química , Sequência de Aminoácidos , Animais , Fator Natriurético Atrial/genética , Células CHO , Cricetinae , Dados de Sequência Molecular , Mutagênese
16.
J Med Chem ; 45(4): 881-7, 2002 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-11831899

RESUMO

Analogues of mini atrial natriuretic peptide (miniANP) that provide conformational properties related to biological activity were designed on the basis of the structure revealed by NMR and restrained molecular dynamics (rMD) simulation, and an analogue with a high level of biological activity was successfully obtained. MiniANP is a cyclic pentadecapeptide analogue of atrial natriuretic polypeptide (ANP). The conformation of miniANP analyzed by NMR and rMD simulation indicated that positive phi angles are preferred for Gly(5) and Gly(6), which is typical for D-amino acids. On the basis of the structural information, [D-Ala(5)]miniANP, [D-Ala(6)]miniANP, and [D-Ala(5) D-Ala(6)]miniANP were synthesized. The biological activity of [D-Ala(5)]miniANP was stronger than that of miniANP, confirming that Gly(5) of miniANP takes a positive phi angle on binding to the receptor. Conformational analysis of these analogue peptides by NMR suggested that a turnlike conformation at residues 6-9 and a proximate pair formed by side chains of Phe(4) and Ile(11) are important for the biological activity.


Assuntos
Fator Natriurético Atrial/química , Oligopeptídeos/síntese química , Peptídeos Cíclicos/síntese química , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Células CHO , Cricetinae , AMP Cíclico/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Dados de Sequência Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Conformação Proteica , Soluções
17.
Photochem Photobiol ; 76(6): 606-15, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12511040

RESUMO

Ring-fused retinal analogs were designed to examine the hula-twist mode of the photoisomerization of the 9-cis retinylidene chromophore. Two 9-cis retinal analogs, the C11-C13 five-membered ring-fused and the C12-C14 five-membered ring-fused retinal derivatives, formed the pigments with opsin. The C11-C13 ring-fused analog was isomerized to a relaxed all-trans chromophore (lambda(max) > 400 nm) at even -269 degrees C and the Schiff base was kept protonated at 0 degrees C. The C12-C14 ring-fused analog was converted photochemically to a bathorhodopsin-like chromophore (lambda(max) = 583 nm) at -196 degrees C, which was further converted to the deprotonated Schiff base at 0 degrees C. The model-building study suggested that the analogs do not form pigments in the retinal-binding site of rhodopsin but form pigments with opsin structures, which have larger binding space generated by the movement of transmembrane helices. The molecular dynamics simulation of the isomerization of the analog chromophores provided a twisted C11-C12 double bond for the C12-C14 ring-fused analog and all relaxed double bonds with a highly twisted C10-C11 bond for the C11-C13 ring-fused analog. The structural model of the C11-C13 ring-fused analog chromophore showed a characteristic flip of the cyclohexenyl moiety toward transmembrane segments 3 and 4. The structural models suggested that hula twist is a primary process for the photoisomerization of the analog chromophores.


Assuntos
Retinaldeído/análogos & derivados , Retinaldeído/química , Opsinas de Bastonetes/química , Cromatografia Líquida de Alta Pressão , Ligantes , Estrutura Molecular , Fotoquímica , Retinaldeído/síntese química , Análise Espectral , Temperatura
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