RESUMO
A series of N1 acetamide substituted naphthyridinone HIV-1 integrase inhibitors have been explored to understand structure-activity relationships (SAR) with various C3 amide groups. Investigations were evaluated using integrase enzyme inhibition, antiviral activity and protein binding effects to optimize the sub-structures. Lipophilicity was also incorporated to understand ligand lipophilic efficiency as a function of the structural modifications. Three representative analogs were further examined in a peripheral blood mononuclear cell (PBMC) antiviral assay as well as in vitro and in vivo drug metabolism and pharmacokinetic studies.
Assuntos
Acetamidas/química , Amidas/química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Naftiridinas/farmacologia , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Estrutura Molecular , Naftiridinas/síntese química , Naftiridinas/química , Relação Estrutura-AtividadeRESUMO
Substituent effects of a series of N1 protio and methyl naphthyridinone HIV-1 integrase strand-transfer inhibitors has been explored. The effects of combinations of the N1 substituent and C3 amide groups was extensively studied to compare enzyme inhibition, antiviral activity and protein binding effects on potency. The impact of substitution on ligand efficiency was considered and several compounds were advanced into in vivo pharmacokinetic studies ultimately leading to the clinical candidate GSK364735.
Assuntos
Amidas/química , Naftiridinas/química , Bioensaio , Ativação Enzimática/efeitos dos fármacos , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Naftiridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Several series of CCR5 antagonists have been discovered by derivatization at the N-terminal of the piperidine ring of the core template 2. Some derivatives exhibited potent inhibition against HIV-1infection. The pharmacokinetic properties of the lead compounds 11a, 14a, 15b, and 16b have been evaluated in vivo.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Infecções por HIV/tratamento farmacológico , Piperidinas/síntese química , Animais , Fármacos Anti-HIV/farmacologia , Células CHO , Química Farmacêutica/métodos , Cricetinae , Cricetulus , Desenho de Fármacos , HIV-1/metabolismo , Concentração Inibidora 50 , Conformação Molecular , Piperidinas/farmacologia , Estrutura Terciária de Proteína , Ratos , Receptores CCR5/químicaRESUMO
Structure-activity relationships in rhesus monkeys for a novel mixed-onium class of ultra-short-acting nondepolarizing tetrahydroisoquinolinium neuromuscular blockers (NMBs) are described. Bis-onium chlorofumarate 20a with (1R,2S)-benzyltetrahydroisoquinolinium groups was a potent lead compound (ED(95) = 0.079 mg/kg) with an ultra-short duration of NMB effect (7.1 min) and a selectivity index (SI: defined as a ratio of the cardiovascular threshold dose to the ED(95)) similar to that of mivacurium (3). The mean threshold dose for cardiovascular effects with 20a was ca. 20 times its ED(95) value (SI = 20). A novel mixed-onium analogue of 20a was prepared by replacing the benzyltetrahydroisoquinolinium group distal to the fumarate chlorine atom with a (1S,2R)-phenyltetrahydroisoquinolinium moiety. The resulting mixed-onium chlorofumarate 24a displayed good NMB potency (ED(95) = 0.063 mg/kg), ultra-short duration of action (5.6 min) and an improved selectivity index (SI = 57). Several other mixed-onium derivatives containing octanedioate (25a; ED(95) = 0.103 mg/kg), difluorosuccinate (27c; ED(95) = 0.056 mg/kg), and fluorofumarate (28a; ED(95) = 0.137 mg/kg) linkers were also potent, ultra-short-acting NMBs with good to excellent selectivity index values (SI = 37-96). Octanedioate 25a was longer acting at higher doses compared to difluorosuccinate 27c and chlorofumarate 24a. Durations of NMB effect following a 0.4 mg/kg bolus dose (100% block) of 25a, 27c, and 24a were 16.9, 13.0, and 10.0 min, respectively. Recovery time for mixed-onium chlorofumarate 24a following a 1 h continuous infusion at 10-20 microg/kg/min (95-100% block) was ca. 5 min which is similar to that observed following a 0.2 mg/kg bolus dose of this compound and indicates a lack of cummulative effects. Preliminary studies with chlorofumarate 24a in whole human blood revealed that mixed-onium thiazolidine 29 was the major metabolite and that plasma cholinesterases do not play the primary role in duration of NMB effect. The NMB properties of 24a in rhesus monkeys led to its clinical evaluation as a possible alternative to succinylcholine.
Assuntos
Anisóis/síntese química , Fumaratos/síntese química , Isoquinolinas/síntese química , Bloqueadores Neuromusculares/síntese química , Compostos de Amônio Quaternário/síntese química , Succinatos/síntese química , Animais , Anisóis/sangue , Anisóis/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fumaratos/sangue , Fumaratos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Técnicas In Vitro , Isoquinolinas/sangue , Isoquinolinas/química , Isoquinolinas/farmacologia , Macaca mulatta , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Bloqueadores Neuromusculares/sangue , Bloqueadores Neuromusculares/farmacologia , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Succinatos/sangue , Succinatos/farmacologiaRESUMO
A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.
Assuntos
Antivirais/farmacologia , Ácidos Borônicos/química , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Antivirais/química , Descoberta de Drogas , Farmacorresistência Viral/genética , Hepacivirus/enzimologia , Hepacivirus/genética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Antagonistas dos Receptores CCR5 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Piperidinas/química , Piperidinas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Área Sob a Curva , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/metabolismo , Benzimidazóis , Cães , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Haplorrinos , Humanos , Piperidinas/síntese química , Piperidinas/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas , TropanosRESUMO
The medicinal chemistry and structure-activity relationships for a novel series of 7-benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV-integrase inhibitors are disclosed. Substituent effects were evaluated at the N-1, C-3, and 7-benzyl positions of the naphthyridinone ring system. Low nanomolar IC(50) values were achieved in an HIV-integrase strand transfer assay with both carboxylic ester and carboxamide groups at C-3. More importantly, several carboxamide congeners showed potent antiviral activity in cellular assays. A 7-benzyl substituent was found to be critical for potent enzyme inhibition, and an N-(2-methoxyethyl)carboxamide moiety at C-3 significantly reduced plasma protein binding effects in vitro. Pharmacokinetic data in rats for one carboxamide analogue demonstrated oral bioavailability and reasonable in vivo clearance.
Assuntos
Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV/enzimologia , Naftiridinas/química , Naftiridinas/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/farmacocinética , Antivirais/farmacologia , Ácidos Carboxílicos/química , Ésteres/química , HIV/efeitos dos fármacos , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacocinética , Masculino , Taxa de Depuração Metabólica , Naftiridinas/síntese química , Naftiridinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC 50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC 50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , HIV-1/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores CCR5/química , Receptores CCR5/metabolismo , Antivirais/química , Avaliação Pré-Clínica de Medicamentos , Ligantes , Estrutura Molecular , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration +/- standard deviation, 8 +/- 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd [binding constant], 6 +/- 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 +/- 0.4 and 5 +/- 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Naftiridinas/farmacologia , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Células Cultivadas , Farmacorresistência Viral , Sinergismo Farmacológico , Integrase de HIV/genética , Inibidores da Protease de HIV/farmacologia , HIV-1/enzimologia , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/virologia , Testes de Sensibilidade Microbiana/métodos , Mutação , Inibidores da Transcriptase Reversa/farmacologia , Integração Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
An efficient synthesis of methyl 7-hydroxy[1,3]thiazolo[5,4-b]pyridin-5(4H)-one-6-carboxylates (8-10 and 16) and 6-carboxamides (17-20) is described. Sub-micromolar enzyme inhibition of HIV integrase was achieved with several carboxamide analogs which were superior to their carboxylic ester congeners.