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1,3,8-Triazaspiro[4.5]decane-2,4-diones as efficacious pan-inhibitors of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) for the treatment of anemia.
J Med Chem ; 55(7): 2945-59, 2012 Apr 12.
Article em En | MEDLINE | ID: mdl-22364528
ABSTRACT
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

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Compostos de Espiro / Compostos Aza / Pró-Colágeno-Prolina Dioxigenase / Fator 1 Induzível por Hipóxia / Hidantoínas / Anemia Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Compostos de Espiro / Compostos Aza / Pró-Colágeno-Prolina Dioxigenase / Fator 1 Induzível por Hipóxia / Hidantoínas / Anemia Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2012 Tipo de documento: Article