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1.
ACS Med Chem Lett ; 7(8): 797-801, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27563405

RESUMO

Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase. Combination of these lessons led to the discovery of compound 20, having balanced serum-shifted antiviral potency and minimized excretion in to the biliary tract in rat, potentially representing a clinically viable starting point for a new treatment option for individuals infected with HIV.

2.
ACS Med Chem Lett ; 5(4): 422-7, 2014 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-24900852

RESUMO

An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.

3.
ACS Med Chem Lett ; 5(6): 711-6, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24944749

RESUMO

A scaffold replacement approach was used to identifying the pyridine series of noncatalytic site integrase inhibitors. These molecules bind with higher affinity to a tetrameric form compared to a dimeric form of integrase. Optimization of the C6 and C4 positions revealed that viruses harboring T124 or A124 amino acid substitutions are highly susceptible to these inhibitors, but viruses having the N124 amino acid substitution are about 100-fold less susceptible. Compound 20 had EC50 values <10 nM against viruses having T124 or A124 substitutions in IN and >800 nM in viruses having N124 substitions. Compound 20 had an excellent in vitro ADME profile and demonstrated reduced contribution of biliary excretion to in vivo clearance compared to BI 224436, the lead compound from the quinoline series of NCINIs.

4.
Bioorg Med Chem Lett ; 23(14): 4267-71, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23735741

RESUMO

In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4-proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported.


Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Prolina/análogos & derivados , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Sítios de Ligação , Desenho de Fármacos , Meia-Vida , Hepacivirus/fisiologia , Simulação de Acoplamento Molecular , Prolina/síntese química , Prolina/farmacocinética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
5.
Bioorg Med Chem Lett ; 23(13): 3967-75, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23673016

RESUMO

Recently, a new class of HIV reverse transcriptase (HIV-RT) inhibitors has been reported. The novel mechanism of inhibition by this class involves competitive binding to the active site of the RT enzyme and has been termed Nucleotide-Competing Reverse Transcriptase Inhibitors (NcRTIs). In this publication we describe the optimization of a novel benzofurano[3,2-d]pyrimidin-2-one series of NcRTIs. The starting point for the current study was inhibitor 2, which had high biochemical and antiviral potency but only moderate permeability in a Caco-2 assay and high B-to-A efflux, resulting in moderate rat bioavailability and low Cmax. We present herein the results and strategies we employed to optimize both the potency as well as the permeability, metabolic stability and pharmacokinetic profile of this series. One of the key observations of the present study was the importance of shielding polar functionality, at least in the context of the current chemotype, to enhance permeability. These studies led to the identification of inhibitors 39 and 45, which display sub-nanomolar antiviral potency in a p24 ELISA assay with significantly reduced efflux ratios (ratios <1.5). These inhibitors also display excellent rat pharmacokinetic profiles with high bioavailabilities and low clearance.


Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV/efeitos dos fármacos , Pirimidinonas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/química , Benzofuranos/química , Disponibilidade Biológica , Células CACO-2 , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/administração & dosagem , Pirimidinonas/química , Ratos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 23(9): 2775-80, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23511023

RESUMO

Screening of our sample collection led to the identification of a set of benzofurano[3,2-d]pyrimidine-2-one hits acting as nucleotide-competing HIV-1 reverse transcriptase inhibitiors (NcRTI). Significant improvement in antiviral potency was achieved when substituents were introduced at positions N1, C4, C7 and C8 on the benzofuranopyrimidone scaffold. The series was optimized from low micromolar enzymatic activity against HIV-1 RT and no antiviral activity to low nanomolar antiviral potency. Further profiling of inhibitor 30 showed promising overall in vitro properties and also demonstrated that its potency was maintained against viruses resistant to the other major classes of HIV-1 RT inhibitors.


Assuntos
Benzofuranos/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Nucleotídeos/química , Pirimidinonas/química , Inibidores da Transcriptase Reversa/química , Animais , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Microssomos Hepáticos/metabolismo , Nucleotídeos/metabolismo , Ligação Proteica , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Ratos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
7.
J Med Chem ; 53(17): 6466-76, 2010 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-20715823

RESUMO

C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats.


Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Oligopeptídeos/síntese química , Inibidores de Serina Proteinase/síntese química , Tiazóis/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Ácidos Aminoisobutíricos , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Hepacivirus/genética , Humanos , Leucina/análogos & derivados , Masculino , Microssomos Hepáticos/metabolismo , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Prolina/análogos & derivados , Quinolinas , Ratos , Ratos Sprague-Dawley , Replicon/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia
9.
J Med Chem ; 47(26): 6584-94, 2004 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-15588093

RESUMO

The inadequate efficacy and tolerability of current therapies for the infectious liver disease caused by the hepatitis C virus have warranted significant efforts in the development of new therapeutics. We have previously reported competitive peptide inhibitors of the NS3 serine protease based on the N-terminal cleavage products of peptide substrates. A detailed study of the interactions of these substrate-based inhibitors with the different subsites of the serine protease active site led to the discovery of novel residues that increased the affinity of the inhibitors. In this paper, we report the combination of the best binding residues in a tetrapeptide series that resulted in extremely potent inhibitors that bind exquisitely well to this enzyme. A substantial increase in potency was obtained with the simultaneous introduction of a 7-methoxy-2-phenyl-4-quinolinoxy moiety at the gamma-position of the P2 proline and a tert-leucine as a P3 residue. The increase in potency allowed for the further truncation and led to the identification of tripeptide inhibitors. Structure activity relationship studies on this inhibitor series led to the identification of carbamate-containing tripeptides that are able to inhibit replication of subgenomic HCV RNA in cell culture with potencies below 1 microM. This inhibitor series has the potential of becoming antiviral agents for the treatment of HCV infections.


Assuntos
Antivirais/síntese química , Oligopeptídeos/síntese química , Quinolinas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacologia , Proteínas de Transporte/química , Células Cultivadas , Cristalografia por Raios X , Hepacivirus/genética , Humanos , Ligação de Hidrogênio , Peptídeos e Proteínas de Sinalização Intracelular , Modelos Moleculares , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Ligação Proteica , Quinolinas/química , Quinolinas/farmacologia , RNA Viral/biossíntese , Estereoisomerismo , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química , Proteínas Virais/química
10.
Org Lett ; 6(17): 2901-4, 2004 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-15330643
11.
J Med Chem ; 47(15): 3788-99, 2004 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15239657

RESUMO

Azapeptides are known inhibitors of several serine and cysteine proteases. In seeking different classes of inhibitors for the HCV serine protease, a series of novel azapeptide-based inhibitors were investigated which incorporated noncleavable P1/P1' aza-amino acyl residues. Extensive SAR studies around the P1/P1' aza-amino acyl fragment resulted in the identification of potent and selective inhibitors. Using NMR studies, we have shown that this series of inhibitors bind in a noncovalent competitive fashion to the NS3 protease active site. The bound conformation of one of these new azapeptide-based inhibitors was determined using the transfer NOE technique. Incorporation of these new aza-amino acyl functionalities in the P1 position provided a handle to probe for new interactions in the S' region of the enzyme.


Assuntos
Compostos Aza/síntese química , Hepacivirus/química , Peptídeos/síntese química , Serina Endopeptidases/química , Inibidores de Serina Proteinase/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Compostos Aza/química , Sítios de Ligação , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Peptídeos/química , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química
12.
J Med Chem ; 47(7): 1605-8, 2004 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-15027850

RESUMO

From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.


Assuntos
Antivirais/síntese química , Carbamatos/síntese química , Hepacivirus/enzimologia , Compostos Heterocíclicos/síntese química , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/química , Antivirais/farmacologia , Disponibilidade Biológica , Carbamatos/química , Carbamatos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Injeções Intravenosas , Prolina/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade
13.
J Biol Chem ; 278(22): 20374-80, 2003 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-12646587

RESUMO

The hepatitis C virus (HCV) NS3 protease is essential for polyprotein maturation and viral propagation, and it has been proposed as a suitable target for antiviral drug discovery. An N-terminal hexapeptide cleavage product of a dodecapeptide substrate identified as a weak competitive inhibitor of the NS3 protease activity was optimized to a potent and highly specific inhibitor of the enzyme. The effect of this potent NS3 protease inhibitor was evaluated on replication of subgenomic HCV RNA and compared with interferon-alpha (IFN-alpha), which is currently used in the treatment of HCV-infected patients. Treatment of replicon-containing cells with the NS3 protease inhibitor or IFN-alpha showed a dose-dependent decrease in subgenomic HCV RNA that reached undetectable levels following a 14-day treatment. Kinetic studies in the presence of either NS3 protease inhibitor or IFN-alpha also revealed similar profiles in HCV RNA decay with half-lives of 11 and 14 h, respectively. The finding that an antiviral specifically targeting the NS3 protease activity inhibits HCV RNA replication further validates the NS3 enzyme as a prime target for drug discovery and supports the development of NS3 protease inhibitors as a novel therapeutic approach for HCV infection.


Assuntos
Hepacivirus/efeitos dos fármacos , RNA Viral/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , Antivirais/uso terapêutico , Hepacivirus/enzimologia , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , RNA Viral/biossíntese , Inibidores de Serina Proteinase/uso terapêutico
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