RESUMO
Discovery of potent renin inhibitors which contain a simplified alkylamino Asp-binding group and exhibit improved selectivity for renin over Cyp3A4 is described. Structure-function results in this series are rationalized based on analysis of selected compounds bound to renin, and the contribution of each molecular feature leading to the reduced P450 inhibition is quantified.
Assuntos
Ácido Aspártico/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inibidores de Proteases/química , Renina/antagonistas & inibidores , Ácido Aspártico/química , Sítios de Ligação , Cristalografia por Raios X , Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Simulação de Dinâmica Molecular , Inibidores de Proteases/metabolismo , Ligação Proteica , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of azepanone inhibitors of cathepsin S is described. Selectivity over both cathepsin K and cathepsin L was achieved by varying the P2 substituent. Ultimately, a balanced potency and selectivity profile was achieved in compound 39 possessing a 1-methylcyclohexyl alanine at P2 and nicotinamide as the P' substituent. The cellular potency of selected analogs is also described.
Assuntos
Azepinas/química , Catepsinas/antagonistas & inibidores , Niacinamida/análogos & derivados , Inibidores de Proteases/química , Alanina/química , Azepinas/síntese química , Azepinas/farmacologia , Sítios de Ligação , Catepsina K/antagonistas & inibidores , Catepsina K/metabolismo , Catepsina L/antagonistas & inibidores , Catepsina L/metabolismo , Catepsinas/metabolismo , Simulação por Computador , Humanos , Niacinamida/síntese química , Niacinamida/química , Niacinamida/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.2 mL/min/kg). Of particular note, the 4S-7-cis-methylazepanone analogue, 10, had a K(i,app) = 0.041 nM vs human cathepsin K and 89% oral bioavailability and an in vivo clearance rate of 19.5 mL/min/kg in the rat. Hypotheses that rationalize some of the observed characteristics of these closely related analogues have been made using X-ray crystallography and conformational analysis. These examples demonstrate the potential for modulation of pharmacological properties of cathepsin inhibitors by substituting the azepanone core. The high potency for inhibition of cathepsin K coupled with the favorable rat and monkey pharmacokinetic characteristics of compound 10, also known as SB-462795 or relacatib, has made it the subject of considerable in vivo evaluation for safety and efficacy as an inhibitor of excessive bone resorption in rat, monkey, and human studies, which will be reported elsewhere.
Assuntos
Azepinas/síntese química , Conservadores da Densidade Óssea/síntese química , Catepsinas/antagonistas & inibidores , Sulfonas/síntese química , Animais , Azepinas/química , Azepinas/farmacologia , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Catepsina K , Catepsinas/química , Linhagem Celular , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Haplorrinos , Humanos , Conformação Molecular , Ligação Proteica , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
The extension of a previously reported cathepsin K azepanone-based inhibitor template to the design and synthesis of potent and selective inhibitors of the homologous cysteine protease cathepsin L is detailed. Structure-activity studies examining the effect of inhibitor selectivity as a function of the P3 and P2 binding elements of the potent cathepsin K inhibitor 1 revealed that incorporation of either a P3 quinoline-8-carboxamide or a naphthylene-1-carboxamide led to increased selectivity for cathepsin L over cathepsin K. Substitution of the P2 leucine of 1 with either a phenylalanine or a beta-naphthylalanine also resulted in an increased selectivity for cathepsin L over cathepsin K. Molecular modeling studies with the inhibitors docked within the active sites of both cathepsins L and K have rationalized the observed selectivities. Optimization of cathepsin L binding by the combination of the P3 naphthylene-1-carboxamide with the P2 beta-naphthylalanine provided 15, which is a potent, selective, and competitive inhibitor of human cathepsin L with a K(i) = 0.43 nM.
Assuntos
Azepinas/síntese química , Catepsinas/antagonistas & inibidores , Catepsinas/química , Cisteína Endopeptidases/química , Inibidores de Cisteína Proteinase/síntese química , Sulfonas/síntese química , Amidas/química , Azepinas/química , Sítios de Ligação , Catepsina L , Inibidores de Cisteína Proteinase/química , Humanos , Modelos Moleculares , Quinolinas/química , Relação Estrutura-Atividade , Sulfonas/químicaRESUMO
Inhibitors of human methionine aminopeptidase type 2 (hMetAP2) are of interest as potential treatments for cancer. A new class of small molecule reversible inhibitors of hMetAP2 was discovered and optimized, the 4-aryl-1,2,3-triazoles. Compound 24, a potent inhibitor of cobalt-activated hMetAP2, also inhibits human and mouse endothelial cell growth. Using a mouse matrigel model, this reversible hMetAP2 inhibitor was also shown to inhibit angiogenesis in vivo.
Assuntos
Aminopeptidases/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Metaloendopeptidases/antagonistas & inibidores , Triazóis/síntese química , Aminopeptidases/química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Sítios de Ligação , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cobalto/metabolismo , Colágeno , Cristalografia por Raios X , Combinação de Medicamentos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Ativação Enzimática , Humanos , Laminina , Metaloendopeptidases/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Proteoglicanas , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
We report the synthesis and biological activity of a series of 2-cyano-4-fluoro-1-thiovalylpyrrolidine inhibitors of DPP-IV. Within this series, compound 19 provided a potent, selective, and orally active DPP-IV inhibitor which demonstrated a very long duration of action in both rat and dog.