RESUMO
We hereby disclose the discovery of inhibitors of CaMKII (7h and 7i) that are highly potent in rat ventricular myocytes, selective against hERG and other off-target kinases, while possessing good CaMKII tissue isoform selectivity (cardiac γ/δ vs. neuronal α/ß). In vitro and in vivo ADME/PK studies demonstrated the suitability of these CaMKII inhibitors for PO (7h rat Fâ¯=â¯73%) and IV pharmacological studies.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and ß-blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead. Optimization of substituents for Late INa current inhibition and lack of Peak INa inhibition led to the discovery of 4h (GS-458967) with improved anti-arrhythmic activity relative to ranolazine. Unfortunately, 4h demonstrated use dependent block across the sodium isoforms including the central and peripheral nervous system isoforms that is consistent with its low therapeutic index (approximately 5-fold in rat, 3-fold in dog). Compound 4h represents our initial foray into a 2nd generation Late INa inhibitor program and is an important proof-of-concept compound. We will provide additional reports on addressing the CNS challenge in a follow-up communication.
Assuntos
Descoberta de Drogas , Coração/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Piridinas/farmacologia , Ranolazina/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Triazóis/farmacologia , Animais , Células CACO-2 , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Macaca fascicularis , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Coelhos , Ranolazina/síntese química , Ranolazina/química , Ratos , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
Previously we disclosed the discovery of potent Late INa current inhibitor 2 (GS-458967, IC50 of 333nM) that has a good separation of late versus peak Nav1.5 current, but did not have a favorable CNS safety window due to high brain penetration (3-fold higher partitioning into brain vs plasma) coupled with potent inhibition of brain sodium channel isoforms (Nav1.1, 1.2, 1.3). We increased the polar surface area from 50 to 84Å(2) by adding a carbonyl to the core and an oxadiazole ring resulting in 3 GS-462808 that had lower brain penetration and serendipitously lower activity at the brain isoforms. Compound 3 has an improved CNS window (>20 rat and dog) relative to 2, and improved anti-ischemic potency relative to ranolazine. The development of 3 was not pursued due to liver lesions in 7day rat toxicology studies.