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1.
J Med Chem ; 60(12): 4932-4948, 2017 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-28537398

RESUMO

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Actinas/antagonistas & inibidores , Adamantano/administração & dosagem , Adamantano/química , Adamantano/farmacologia , Administração Oral , Animais , Azetidinas/administração & dosagem , Azetidinas/química , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Feminino , Meia-Vida , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Camundongos Obesos , Ratos , Relação Estrutura-Atividade
2.
J Mol Biol ; 427(4): 924-942, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25579995

RESUMO

The human pregnane X receptor (PXR) is a promiscuous nuclear receptor that functions as a sensor to a wide variety of xenobiotics and regulates expression of several drug metabolizing enzymes and transporters. We have generated "Adnectins", derived from 10th fibronectin type III domain ((10)Fn3), that target the PXR ligand binding domain (LBD) interactions with the steroid receptor co-activator-1 (SRC-1) peptide, displacing SRC-1 binding. Adnectins are structurally homologous to the immunoglobulin superfamily. Three different co-crystal structures of PXR LBD with Adnectin-1 and CCR1 (CC chemokine receptor-1) antagonist Compound-1 were determined. This structural information was used to modulate PXR affinity for a related CCR1 antagonist compound that entered into clinical trials for rheumatoid arthritis. The structures of PXR with Adnectin-1 reveal specificity of Adnectin-1 in not only targeting the interface of the SRC-1 interactions but also engaging the same set of residues that are involved in binding of SRC-1 to PXR. Substituting SRC-1 with Adnectin-1 does not alter the binding conformation of Compound-1 in the ligand binding pocket. The structure also reveals the possibility of using Adnectins as crystallization chaperones to generate structures of PXR with compounds of interest.


Assuntos
Coativador 1 de Receptor Nuclear/química , Receptores CCR1/antagonistas & inibidores , Receptores de Esteroides/química , Ureia/análogos & derivados , Valina/análogos & derivados , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Humanos , Lignanas/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Receptor de Pregnano X , Ligação Proteica , Estrutura Terciária de Proteína , Receptores CCR1/metabolismo , Alinhamento de Sequência , Ressonância de Plasmônio de Superfície , Ureia/química , Ureia/metabolismo , Ureia/farmacologia , Valina/química , Valina/metabolismo , Valina/farmacologia
3.
J Med Chem ; 57(18): 7550-64, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25101488
4.
ACS Med Chem Lett ; 5(7): 803-8, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25050169

RESUMO

Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11ß-hydroxysteroid dehydrogenase-type 1 (11ß-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11ß-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

5.
J Med Chem ; 57(5): 1855-79, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24397558

RESUMO

Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.


Assuntos
Antivirais/farmacologia , Benzazepinas/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Animais , Antivirais/química , Antivirais/farmacocinética , Benzazepinas/química , Benzazepinas/farmacocinética , Cães , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Indóis/química , Indóis/farmacocinética , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Ratos , Relação Estrutura-Atividade
6.
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
7.
Bioorg Med Chem Lett ; 21(22): 6909-15, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21974952
8.
Bioorg Med Chem Lett ; 21(22): 6693-8, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21983444

RESUMO

Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11ß-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Humanos , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 21(22): 6916-24, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21782431

RESUMO

The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lactamas/química , Lactamas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Animais , Cristalografia por Raios X , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Lactamas/síntese química , Lactamas/farmacocinética , Camundongos , Modelos Moleculares , Ratos , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 21(10): 2925-9, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21486696

RESUMO

Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC(50)=0.07 µM, %F=18), are reported.


Assuntos
Ativação Enzimática/efeitos dos fármacos , Hepacivirus/enzimologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Indóis/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Desenho de Drogas , Compostos Heterocíclicos/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 21(1): 537-41, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21078556

RESUMO

Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aß levels, but did not lower rat brain Aß due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1.


Assuntos
Aminas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Indóis/síntese química , Inibidores de Proteases/química , Piridinas/síntese química , Aminas/síntese química , Aminas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/sangue , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Indóis/química , Indóis/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 18(11): 3168-72, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18485702

RESUMO

Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Amidas/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Conformação Molecular , Estrutura Molecular , Piridinas/química , Relação Estrutura-Atividade
13.
Arch Biochem Biophys ; 410(2): 307-16, 2003 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-12573291

RESUMO

Amyloid precursor protein (APP) cleaving enzyme (BACE) is the enzyme responsible for beta-site cleavage of APP, leading to the formation of the amyloid-beta peptide that is thought to be pathogenic in Alzheimer's disease (AD). Hence, BACE is an attractive pharmacological target, and numerous research groups have begun searching for potent and selective inhibitors of this enzyme as a potential mechanism for therapeutic intervention in AD. The mature enzyme is composed of a globular catalytic domain that is N-linked glycosylated in mammalian cells, a single transmembrane helix that anchors the enzyme to an intracellular membrane, and a short C-terminal domain that extends outside the phospholipid bilayer of the membrane. Here we have compared the substrate and active site-directed inhibitor binding properties of several recombinant constructs of human BACE. The constructs studied here address the importance of catalytic domain glycosylation state, inclusion of domains other than the catalytic domain, and incorporation into a membrane bilayer on the interactions of the enzyme active site with peptidic ligands. We find no significant differences in ligand binding properties among these various constructs. These data demonstrate that the nonglycosylated, soluble catalytic domain of BACE faithfully reflects the ligand binding properties of the full-length mature enzyme in its natural membrane environment. Thus, the use of the nonglycosylated, soluble catalytic domain of BACE is appropriate for studies aimed at understanding the determinants of ligand recognition by the enzyme active site.


Assuntos
Ácido Aspártico Endopeptidases/química , Proteínas Recombinantes/química , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Células CHO , Catálise , Domínio Catalítico , Linhagem Celular , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Cricetinae , Relação Dose-Resposta a Droga , Drosophila , Endopeptidases , Escherichia coli/metabolismo , Glicosilação , Humanos , Concentração Inibidora 50 , Cinética , Ligantes , Luz , Bicamadas Lipídicas/metabolismo , Peptídeos/química , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/metabolismo , Espalhamento de Radiação , Fatores de Tempo
14.
Chem Biol ; 9(1): 79-92, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11841941

RESUMO

NMR spectroscopy was used to characterize the hepatitis C virus (HCV) NS3 protease in a complex with the 24 residue peptide cofactor from NS4A and a boronic acid inhibitor, Ac-Asp-Glu-Val-Val-Pro-boroAlg-OH. Secondary-structure information, NOE constraints between protease and cofactor, and hydrogen-deuterium exchange rates revealed that the cofactor was an integral strand in the N-terminal beta-sheet of the complex as observed in X-ray crystal structures. Based upon chemical-shift perturbations, inhibitor-protein NOEs, and the protonation state of the catalytic histidine, the boronic acid inhibitor was bound in the substrate binding site as a transition state mimic. In the absence of cofactor, the inhibitor had a lower affinity for the protease. Although the inhibitor binds in the same location, differences were observed at the catalytic site of the protease.


Assuntos
Ácidos Borônicos/química , Proteínas de Transporte/química , Hepacivirus/enzimologia , Inibidores de Proteases/química , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/química , Sítios de Ligação , Ácidos Borônicos/farmacologia , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Inibidores de Proteases/farmacologia
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