RESUMO
The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
Assuntos
Anemia/tratamento farmacológico , Compostos Aza/síntese química , Hidantoínas/síntese química , Fator 1 Induzível por Hipóxia/metabolismo , Pró-Colágeno-Prolina Dioxigenase/antagonistas & inibidores , Compostos de Espiro/síntese química , Animais , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Cães , Canal de Potássio ERG1 , Eritropoetina/biossíntese , Canais de Potássio Éter-A-Go-Go/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Hidantoínas/farmacocinética , Hidantoínas/farmacologia , Prolina Dioxigenases do Fator Induzível por Hipóxia , Indóis/síntese química , Indóis/farmacocinética , Indóis/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Macaca mulatta , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Regulação para CimaRESUMO
Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.