RESUMO
This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoyl pyridone analogues to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nanomolar potency in standard antiviral assays. An additional hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clinically relevant resistant viruses. These findings led to additional cyclic tethering of the naked hydroxyl group resulting in tricyclic carbamoyl pyridone inhibitors to address remaining issues and deliver potential clinical candidates. The tricyclic carbamoyl pyridone derivatives described herein served as the immediate leads in molecules to the next generation integrase inhibitor dolutegravir which is currently in late stage clinical evaluation.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/efeitos dos fármacos , Piridonas/farmacologia , Animais , Cromatografia Líquida , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacocinética , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Piridonas/química , Piridonas/farmacocinética , RatosRESUMO
We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.
Assuntos
Inibidores de Integrase de HIV/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Piridonas/síntese química , Animais , Cães , Células HeLa , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Macaca fascicularis , Masculino , Oxazinas , Piperazinas , Piridonas/química , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chemistry efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an aromatic group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymatic and antiviral assay formats with low nM IC50 and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concentrations at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.
Assuntos
Antivirais/síntese química , Quelantes/síntese química , HIV-1/enzimologia , Inibidores de Integrase/síntese química , Magnésio/metabolismo , Piridonas/síntese química , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Cátions Bivalentes , Linhagem Celular , Quelantes/farmacocinética , Quelantes/farmacologia , Cães , Desenho de Fármacos , Farmacorresistência Viral , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Inibidores de Integrase/farmacocinética , Inibidores de Integrase/farmacologia , Macaca fascicularis , Modelos Moleculares , Mutação , Piridonas/farmacocinética , Piridonas/farmacologia , RatosRESUMO
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
The two-metal binding model we previously reported as an inhibition mechanism of HIV integrase (HIV IN) produced a new direction in modification of 2-hydroxy-3-heteroaryl acrylic acid inhibitors (HHAAs). Here we present a novel series of HIV IN inhibitors having a 3-hydroxy-1,5-dihydro-pyrrol-2-one moiety (HDPO) as an advanced analog of HHAAs. This cyclic modification of the chelating region of HHAA produces a favorable configuration to coordinate two-metal ions in HIV IN, which consequently gave improvements in not only enzymatic assay but also antiviral cell based assay in many cases.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Pirróis/química , Pirróis/farmacologia , Amidas/química , HIV/efeitos dos fármacos , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Estrutura Molecular , Nitrogênio/química , Pirróis/síntese química , Relação Estrutura-AtividadeRESUMO
We present a novel series of HIV integrase inhibitors, showing IC(50)s ranging from 0.01 to over 370microM in an enzymatic assay. Furthermore, pharmacophore modeling study for the inhibitors was carried out to elucidate the structure-activity relationships. Finally, we found a 3D-pharmacophore model, which is composed of a hydrophilic and a hydrophobic domain, providing valuable information for designing other novel types of integrase inhibitors.
Assuntos
Acrilatos/química , Desenho de Fármacos , Inibidores de Integrase de HIV/química , Integrase de HIV/química , HIV-1/efeitos dos fármacos , Modelos Moleculares , Acrilatos/síntese química , Acrilatos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We propose a two-metal binding model as a potential mechanism of chelating inhibitors against HIV integrase (HIV IN) represented by 2-hydroxy-3-heteroaryl acrylic acids (HHAAs). Potential inhibitors would bind to two metal ions in the active site of HIV IN to prevent human DNA from undergoing the integration reaction. Correlation of the results of metal (Mg(2+) and Mn(2+)) titration studies with HIV IN inhibition for a series of active and inactive compounds provides support for the model. Results suggest Mg(2+) is an essential cofactor for chelating inhibitors.