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1.
J Med Chem ; 62(7): 3254-3267, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30763090

RESUMO

We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), a sulfonamide- N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons. An X-ray structure of NS5B protein cocrystallized with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water molecules and the first evidence of boronate complex formation within the binding pocket. In clinical studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV-infected patients, thereby validating our hypothesis that reducing benzylic oxidation would improve human pharmacokinetics and lower efficacious doses relative to 1.


Assuntos
Antivirais/farmacologia , Ácidos Borônicos/farmacologia , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico/farmacologia , Animais , Antivirais/química , Antivirais/farmacocinética , Ácidos Borônicos/química , Ácidos Borônicos/farmacocinética , Cristalografia por Raios X , Cães , Meia-Vida , Humanos , Macaca fascicularis , Camundongos , Estrutura Molecular , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacocinética , Ratos
2.
Bioorg Med Chem Lett ; 24(10): 2288-94, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24731273

RESUMO

Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5nM and 1.2nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50's of 10.9nM and 6.1nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50's=10.2 and 30.4nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein.


Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/fisiologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Antivirais/síntese química , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Hepacivirus/metabolismo , Humanos , Terapia de Alvo Molecular , Compostos de Espiro/síntese química
3.
J Med Chem ; 57(5): 2107-20, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-23544424

RESUMO

We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacocinética , Área Sob a Curva , Modelos Animais de Doenças , Hepacivirus/fisiologia , Hepatite C/virologia , Camundongos , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia
4.
ACS Med Chem Lett ; 3(7): 565-9, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900511

RESUMO

A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This series demonstrates potent in vitro inhibition of HCV replication (EC50 < 10 nM), direct binding to purified NS4B protein (IC50 < 20 nM), and an HCV resistance pattern associated with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV clinical assets, suggestive of the potential for additive or synergistic combination with other small molecule inhibitors of HCV replication.

5.
Bioorg Med Chem Lett ; 16(17): 4554-8, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16784854

RESUMO

As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure-activity relationships of this class of molecules were explored. Compound 1k, with EC(50) of 270 nM and GI(50) of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid.


Assuntos
Amidas/química , Amidas/farmacologia , Apoptose/efeitos dos fármacos , Oxazóis/química , Oxazóis/farmacologia , Amidas/síntese química , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Estrutura Molecular , Oxazóis/síntese química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Mol Biol ; 329(1): 93-120, 2003 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-12742021

RESUMO

An extensive structural manifold of short hydrogen bond-mediated, active site-directed, serine protease inhibition motifs is revealed in a set of over 300 crystal structures involving a large suite of small molecule inhibitors (2-(2-phenol)-indoles and 2-(2-phenol)-benzimidazoles) determined over a wide range of pH (3.5-11.4). The active site hydrogen-bonding mode was found to vary markedly with pH, with the steric and electronic properties of the inhibitor, and with the type of protease (trypsin, thrombin or urokinase type plasminogen activator (uPA)). The pH dependence of the active site hydrogen-bonding motif is often intricate, constituting a distinct fingerprint of each complex. Isosteric replacements or minor substitutions within the inhibitor that modulate the pK(a) of the phenol hydroxyl involved in short hydrogen bonding, or that affect steric interactions distal to the active site, can significantly shift the pH-dependent structural profile characteristic of the parent scaffold, or produce active site-binding motifs unique to the bound analog. Ionization equilibria at the active site associated with inhibitor binding are probed in a series of the protease-inhibitor complexes through analysis of the pH dependence of the structure and environment of the active site-binding groups involved in short hydrogen bond arrays. Structures determined at high pH (>11), suggest that the pK(a) of His57 is dramatically elevated, to a value as high as approximately 11 in certain complexes. K(i) values involving uPA and trypsin determined as a function of pH for a set of inhibitors show pronounced parabolic pH dependence, the pH for optimal inhibition governed by the pK(a) of the inhibitor phenol involved in short hydrogen bonds. Comparison of structures of trypsin, thrombin and uPA, each bound by the same inhibitor, highlights important structural variations in the S1 and active sites accessible for engineering notable selectivity into remarkably small molecules with low nanomolar K(i) values.


Assuntos
Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Trombina/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Sítios de Ligação , Bovinos , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Cinética , Modelos Moleculares , Conformação Proteica , Eletricidade Estática , Relação Estrutura-Atividade , Trombina/química , Tripsina/química , Inibidores da Tripsina/química , Inibidores da Tripsina/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/química
8.
J Org Chem ; 64(6): 2140-2144, 1999 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-11674316
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