RESUMO
A series of (3R,4R)-pyrrolidine-3,4-dicarboxylic acid amides was investigated with respect to their factor Xa inhibitory activity, selectivity, pharmacokinetic properties, and ex vivo antithrombotic activity. The clinical candidate from this series, R1663, exhibits excellent selectivity against a panel of serine proteases and good pharmacokinetic properties in rats and monkeys. A Phase I clinical study with R1663 has been finalized.
Assuntos
Inibidores do Fator Xa , Pirrolidinas/farmacologia , Pirrolidinas/químicaRESUMO
Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( Ki < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.
Assuntos
Catepsina L/antagonistas & inibidores , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Lactamas Macrocíclicas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Cisteína Endopeptidases/química , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacocinética , Reposicionamento de Medicamentos , Humanos , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacocinética , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Suínos , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/farmacocinéticaRESUMO
Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50,000-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand-receptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Animais , Ciclopentanos/química , Inibidores de Cisteína Proteinase/farmacocinética , Humanos , Camundongos , Prolina/análogos & derivados , Relação Estrutura-AtividadeRESUMO
In two series of small-molecule ligands, one inhibiting human cathepsinâ L (hcatL) and the other MEK1 kinase, biological affinities were found to strongly increase when an aryl ring of the inhibitors is substituted with the larger halogens Cl, Br, and I, but to decrease upon F substitution. X-ray co-crystal structure analyses revealed that the higher halides engage in halogen bonding (XB) with a backbone C=O in the S3â pocket of hcatL and in a back pocket of MEK1. While the S3â pocket is located at the surface of the enzyme, which provides a polar environment, the back pocket in MEK1 is deeply buried in the protein and is of pronounced apolar character. This study analyzes environmental effects on XB in protein-ligand complexes. It is hypothesized that energetic gains by XB are predominantly not due to water replacements but originate from direct interactions between the XB donor (Caryl-X) and the XB acceptor (C=O) in the correct geometry. New X-ray co-crystal structures in the same crystal form (space group P2(1)2(1)2(1)) were obtained for aryl chloride, bromide, and iodide ligands bound to hcatL. These high-resolution structures reveal that the backbone C=O group of Gly61 in most hcatL co-crystal structures maintains water solvation while engaging in XB. An aryl-CF3-substituted ligand of hcatL with an unexpectedly high affinity was found to adopt the same binding geometry as the aryl halides, with the CF3 group pointing to the C=O group of Gly61 in the S3â pocket. In this case, a repulsive F2C-Fâ â â O=C contact apparently is energetically overcompensated by other favorable protein-ligand contacts established by the CF3 group.
Assuntos
Catepsina L/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Halogênios/química , MAP Quinase Quinase 1/metabolismo , Domínio Catalítico , Catepsina L/antagonistas & inibidores , Catepsina L/química , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Ligantes , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/química , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Starting from a hit identified by focused screening, 3-aminopyrrolidine factor Xa inhibitors were designed. The binding mode as determined by X-ray structural analysis as well as the pharmacokinetic behaviour of selected compounds is discussed.
Assuntos
Aminoquinolinas/farmacologia , Antitrombina III/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Fator Xa/metabolismo , Aminoquinolinas/química , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacocinética , Antitrombina III/química , Antitrombina III/metabolismo , Antitrombina III/farmacocinética , Cristalografia por Raios X , Fator Xa/química , Humanos , Modelos Moleculares , Conformação MolecularRESUMO
The synthesis and in vitro structure-activity relationships (SAR) of a series of triazoles as A(2A) receptor antagonists is reported. This resulted in the identification of potent, selective and permeable 1,2,4-triazoles such as 42 for further optimization and evaluation in vivo.