RESUMO
Although the S3 pocket of the thrombin active site is lined with lipophilic amino acid residues, the accommodation of polarity within the lipophilic P3 moiety of small molecule inhibitors is possible provided that the polar functionality is capable of pointing away from the binding pocket outwards toward solvent while simultaneously allowing the lipophilic portion of the P3 ligand to interact with the S3 amino acid residues. Manipulation of this motif provided the means to effect optimization of functional potency, in vivo antithrombotic efficacy and oral bioavailability in a series of 3-aminopyrazinone thrombin inhibitors which contained non-charged groups at the P1 position.
Assuntos
Anticoagulantes/síntese química , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Desenho de Fármacos , Pirazinas/síntese química , Trombina/antagonistas & inibidores , Administração Oral , Animais , Anticoagulantes/química , Anticoagulantes/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Cães , Estrutura Molecular , Pirazinas/química , Pirazinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5-trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency.
Assuntos
Antitrombinas/síntese química , Benzeno/síntese química , Desenho de Fármacos , Trombina/antagonistas & inibidores , Antitrombinas/química , Antitrombinas/farmacologia , Benzeno/química , Benzeno/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.
Assuntos
Anticoagulantes/farmacologia , Antitrombinas/farmacologia , Desenho de Fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Trombina/antagonistas & inibidores , Administração Oral , Animais , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/farmacocinética , Antitrombinas/síntese química , Antitrombinas/química , Antitrombinas/farmacocinética , Disponibilidade Biológica , Cloretos , Cristalografia por Raios X , Cães , Compostos Férricos/farmacologia , Imidazóis/química , Imidazóis/farmacocinética , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Tempo de Tromboplastina Parcial , Ratos , Relação Estrutura-Atividade , Trombina/química , Trombina/metabolismo , Tripsina/metabolismoRESUMO
Despite their relatively weak basicity, simple azoles, specifically imidazoles and aminothiazoles, can function as potent surrogates for the more basic amines (e.g., alkyl amines, amidines, guanidines, etc.) which are most often employed as the P1 ligand in the design of noncovalent small molecule inhibitors of thrombin.
Assuntos
Azóis/farmacologia , Inibidores Enzimáticos/farmacologia , Trombina/antagonistas & inibidores , Azóis/química , Desenho de Fármacos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade , Tripsina/efeitos dos fármacosRESUMO
Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the alpha-thrombin-hirugen complex provides an explanation for these unanticipated results.
Assuntos
Amidas/química , Antitrombinas/farmacologia , Antitrombinas/química , Cristalografia por Raios X , Estrutura MolecularRESUMO
We describe a series of highly potent and efficacious thrombin inhibitors based on a 3-amino-4-sulfonylpyridinone acetamide template. The functionally dense sulfonyl group stabilizes the aminopyridinone, conformationally constrains the 4-substituent, and forms a hydrogen bond to the insertion loop tyrosine OH. We also describe a related series of fused bicyclic dihydrothiadiazinedioxide derivatives, of which one had improved pharmacokinetics in dogs after oral dosing.
Assuntos
Acetamidas/química , Acetamidas/farmacologia , Piridonas/química , Piridonas/farmacologia , Tiadiazinas/química , Tiadiazinas/farmacologia , Trombina/antagonistas & inibidores , Acetamidas/farmacocinética , Administração Oral , Animais , Modelos Animais de Doenças , Cães , Compostos Férricos/toxicidade , Humanos , Modelos Moleculares , Piridonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacocinética , Sulfonas/farmacologia , Tiadiazinas/farmacocinética , Trombose/induzido quimicamente , Inibidores da Tripsina/química , Inibidores da Tripsina/farmacocinética , Inibidores da Tripsina/farmacologiaRESUMO
Use of a chlorophenoxyacetamide P1 group with a pyridinone acetamide P2/P3 gave an exceptionally potent thrombin inhibitor (K(i)=40 pM). Truncation of the molecule at the N-terminus gave unique, low nanomolar, non-covalent thrombin inhibitors which do not have a group to fill thrombin's 'distal binding pocket'. A co-crystal structure indicates the importance of an intramolecular hydrogen bond between the P1 side chain and P1/P2 amide link in this series.