RESUMO
Tertiary hydroxyl class of C-imidazole bridgehead azaheptapyridine FPT inhibitors were prepared in an attempt to block in vivo oxidation of secondary hydroxyl series. One representative compound 5a exhibited potent enzyme (IC50=1.4 nM) and cellular activities (soft agar IC50=1.3 nM) with excellent oral pharmacokinetic profiles in rats, mice, monkeys and dogs. The in vivo study in wap-ras TG mouse models showed dose dependent tumor growth inhibition and regression.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Piridinas/farmacologia , Alquil e Aril Transferases/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/síntese química , Compostos Aza/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Haplorrinos , Humanos , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/patologia , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir1 bound to the NS3 protein suggest that expansion into the S4 pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4 tert-butyl with a cyclohexylmethyl ligand led to inhibitor 2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.
Assuntos
Antivirais/química , Prolina/análogos & derivados , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Área Sob a Curva , Disponibilidade Biológica , Cristalografia por Raios X , Haplorrinos , Modelos Moleculares , Prolina/química , Prolina/farmacocinética , Prolina/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.
Assuntos
Descoberta de Drogas/métodos , Farnesiltranstransferase/antagonistas & inibidores , Imidazóis/química , Piridinas/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Farnesiltranstransferase/metabolismo , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Piridinas/metabolismo , Piridinas/farmacologiaRESUMO
Farnesyl protein transferase (FPT) inhibition is an interesting and promising approach to noncytotoxic anticancer therapy. Research in this area has resulted in several orally active compounds that are in clinical trials. Electrospray ionization (ESI) time-of-flight mass spectrometry (TOF-MS) was used for the direct detection of a 95 182 Da pentameric noncovalent complex of alpha/beta subunits of FPT containing Zn, farnesyl pyrophosphate (FPP) and SCH 66336, a compound currently undergoing phase III clinical trials as an anticancer agent. It was noted that the desalting of protein samples was an important factor in the detection of the complex. This study demonstrated that the presence of FPP in the system was necessary for the detection of the FPT-inhibitor complex. No pentameric complex was detected in the spectrum when the experiment was carried out in the absence of the FPP. An indirect approach was also applied to confirm the noncovalent binding of SCH 66336 to FPT by the use of an off-line size exclusion chromatography followed by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) for the detection of the inhibitor.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Alquil e Aril Transferases/metabolismo , Cromatografia em Gel , Inibidores Enzimáticos/metabolismo , Espectrometria de Massas , Peso Molecular , Piperidinas/metabolismo , Desnaturação Proteica , Piridinas/metabolismo , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
As part of a detailed study, the syntheses, biological activities, and pharmacokinetic properties of hydroxylated analogues of the previously described broad spectrum antifungal agents, Sch 51048 (1), Sch 50001 (3), and Sch 50002 (4), are described. Based on an overall superior profile, one of the alcohols, Sch 56592 (2), was selected for clinical studies.
Assuntos
Antifúngicos/farmacologia , Química Farmacêutica/métodos , Triazóis/química , Triazóis/síntese química , Triazóis/farmacologia , Álcoois , Animais , Antifúngicos/química , Aspergilose/tratamento farmacológico , Candidíase/tratamento farmacológico , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Humanos , Imunossupressores/farmacologia , Camundongos , Modelos Químicos , Fatores de Tempo , Triazóis/farmacocinéticaRESUMO
Hepatitis C virus (HCV) NS3, when bound to NS-4A cofactor, facilitates development of mature virons by catalyzing cleavage of a polyprotein to form functional and structural proteins of HCV. The enzyme has a shallow binding pocket at the catalytic site, making development of inhibitors difficult. We have designed, preorganized, and depeptidized macrocyclic inhibitors from P(4) to P(2)' and optimized binding to 0.1 microM. The structure of an inhibitor bound to the enzyme was also solved.
Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Compostos Macrocíclicos/síntese química , Peptídeos/química , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Ligação de Hidrogênio , Compostos Macrocíclicos/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/química , Ligação Proteica , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/químicaRESUMO
The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen at only one of the two possible ring positions benzylic to the difluorobenzene participates usefully in active site binding.