RESUMO
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
Assuntos
Amidas/síntese química , Aminopiridinas/síntese química , Anticoagulantes/síntese química , Inibidores do Fator Xa , Tiofenos/síntese química , ortoaminobenzoatos/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Cristalografia por Raios X , Cães , Humanos , Técnicas In Vitro , Masculino , Modelos Moleculares , Tempo de Protrombina , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia , Trombose Venosa/tratamento farmacológico , ortoaminobenzoatos/farmacocinética , ortoaminobenzoatos/farmacologiaRESUMO
A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.
Assuntos
Amidas/farmacologia , Inibidores do Fator Xa , Inibidores de Serina Proteinase/farmacologia , Tiofenos/química , Amidas/química , Animais , Cristalografia por Raios X , Cães , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-AtividadeRESUMO
The addition of allylic trichlorosilanes to benzaldehyde promoted by chiral phosphoramides to give the enantioenriched homoallylic alcohol has been investigated. In a survey of Lewis bases as activators for the addition of allyltrichlorosilane to benzaldehyde, phosphorus-based amides have been found to be the most effective promoters. To achieve asymmetric induction, chiral phosphoric triamides derived from chiral diamines have been developed and applied in the allylation reaction albeit with modest enantioselectivities. The addition of 2-butenylsilanes was highly diastereoselective, suggesting a closed, chair-like transition structure. A detailed mechanistic study has been carried out to probe into the origin of activation. From a combination of nonlinear effects and kinetics studies, the reaction was found to likely involve two phosphoramides in both the rate and stereochemistry determining steps. These studies provided the background for the development of highly selective and reactive catalysts.
Assuntos
Aldeídos/química , Amidas/química , Catálise , Ácidos Fosfóricos/química , Silanos/química , Benzaldeídos/química , Crotonatos , Cinética , Fosforamidas , Fósforo , EstereoisomerismoRESUMO
Compound 1 was identified by high throughput screening as a novel PAI-1 inhibitor. Optimization of the B and C-segments of 1 resulted in a series of structurally simplified compounds with improved potency. The synthesis and SAR data of these compounds are presented here.
Assuntos
Metanol/síntese química , Metanol/farmacologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , RatosRESUMO
Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.
Assuntos
Inibidores do Fator Xa , Tiofenos/farmacologia , ortoaminobenzoatos/farmacologia , Animais , Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Bovinos , Compostos Heterocíclicos/farmacologia , Humanos , Indicadores e Reagentes , Cinética , Tempo de Protrombina , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Tiofenos/química , Trombina/antagonistas & inibidores , Inibidores da Tripsina/síntese química , Inibidores da Tripsina/farmacologia , ortoaminobenzoatos/químicaRESUMO
A novel potent and selective aminophenol scaffold for fXa inhibitors was developed from a previously reported benzimidazole-based naphthylamidine template. The aminophenol template is more synthetically accessible than the benzimidazole template, which simplified the introduction of carboxylic acid groups. Substitution of a propenyl-para-hydroxy-benzamidine group on the aminophenol template produced selective, sub-nanomolar fXa inhibitors. The potency of the inhibitors is partially explained with the aid of a trypsin complex crystal structure.
Assuntos
Aminofenóis/química , Aminofenóis/síntese química , Inibidores do Fator Xa , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/síntese química , Difração de Raios XRESUMO
Optimization of the benzimidazole-based fXa inhibitors for selectivity versus thrombin and trypsin was achieved by substitution on the benzimidazole ring and replacement of the naphthylamidine group. Substitution of a nitro group at the 4-position on the benzimidazole improves both potency against fXa and selectivity versus thrombin. Alternatively, replacement of the naphthylamidine with either a biphenylamidine or propenylbenzamidine not only improves fXa potency and selectivity versus thrombin, but selectivity versus trypsin as well.