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1.
Bioorg Med Chem Lett ; 27(15): 3294-3300, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28633899

RESUMO

The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM.


Assuntos
Antivirais/química , Antivirais/farmacologia , Benzazepinas/química , Benzazepinas/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Benzazepinas/farmacocinética , Cães , Haplorrinos , Hepacivirus/enzimologia , Hepacivirus/metabolismo , Hepatite C/virologia , Humanos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , Ratos , Proteínas não Estruturais Virais/metabolismo
2.
ACS Med Chem Lett ; 13(6): 972-980, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35707159

RESUMO

Allosteric HIV-1 integrase inhibitors (ALLINIs) have been of interest recently because of their novel mechanism of action. Strategic modifications to the C5 moiety of a class of 4-(4,4-dimethylpiperidinyl)-2,6-dimethylpyridinyl ALLINIs led to the identification of a tetrahydroisoquinoline heterocycle as a suitable spacer element to project the distal hydrophobic aryl ring. Subsequent optimization of the aryl substitutions identified 12 as an ALLINI with single-digit nanomolar inhibitory potency and low clearance across preclinical species. In preclinical toxicology studies with 12 in rats, lipid hepatocellular vacuolation was observed. Removal of the C6 methyl group resulted in GSK3839919 (22), which exhibited a reduced incidence and severity of lipid vacuolation in both in vitro assays and in vivo studies while maintaining the potency and pharmacokinetic (PK) properties of the prototype. The virology, PK, and toxicology profiles of 22 are discussed.

3.
J Med Chem ; 63(23): 14740-14760, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33226226

RESUMO

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.


Assuntos
Antivirais/farmacologia , Peptídeos Cíclicos/farmacologia , Inibidores de Serina Proteinase/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/metabolismo , Antivirais/farmacocinética , Células CHO , Cricetulus , Descoberta de Drogas , Estabilidade de Medicamentos , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacocinética , Ratos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/metabolismo , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-Atividade
4.
ACS Med Chem Lett ; 9(2): 143-148, 2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29456803

RESUMO

The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH3 and CF3 analogues, respectively, providing insight into the deployment of this unique amino acid.

5.
J Med Chem ; 59(17): 8042-60, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27564532

RESUMO

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).


Assuntos
Antivirais/química , Hepacivirus/efeitos dos fármacos , Isoquinolinas/uso terapêutico , Oligopeptídeos/química , Sulfonamidas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/farmacologia , Cães , Esquema de Medicação , Farmacorresistência Viral , Hepacivirus/genética , Macaca fascicularis , Masculino , Modelos Moleculares , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Coelhos , Ratos Sprague-Dawley , Replicon , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
6.
J Med Chem ; 57(5): 1730-52, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24564672

RESUMO

The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Isoquinolinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/sangue , Antivirais/química , Cães , Humanos , Isoquinolinas/sangue , Isoquinolinas/química , Modelos Moleculares , Inibidores de Proteases/sangue , Inibidores de Proteases/química , Coelhos , Ratos , Sulfonamidas/sangue , Sulfonamidas/química
7.
J Med Chem ; 57(5): 1708-29, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24555570

RESUMO

The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.


Assuntos
Antivirais/uso terapêutico , Descoberta de Drogas , Hepatite C/tratamento farmacológico , Isoquinolinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoquinolinas/química , Modelos Moleculares , Inibidores de Proteases/química , Sulfonamidas/química
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