RESUMO
Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks.
Assuntos
Angioedemas Hereditários , Humanos , Administração Oral , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/metabolismo , Antivirais/uso terapêutico , Ácido Aspártico , Bradicinina/metabolismo , Calicreína PlasmáticaRESUMO
The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.
Assuntos
Asma/tratamento farmacológico , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Asma/metabolismo , Relação Dose-Resposta a Droga , Resistência a Medicamentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Doença Pulmonar Obstrutiva Crônica/metabolismo , Esteroides/farmacologia , Relação Estrutura-Atividade , Células U937RESUMO
A ligand-based approach to identify potential starting points for a dual MCH-1R antagonist/DPPIV inhibitor medicinal chemistry program was undertaken. Potential ligand pairs were identified by analysis of MCH-1R and DPPIV in vitro data. A highly targeted synthetic effort lead to the discovery of pyridone 11, a dual MCH-1R antagonist/DPPIV inhibitor with selectivity over DPP8 and DPP9.
