RESUMEN
Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, IKur, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current IKs, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for IKur over IKs (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans.
Asunto(s)
Canal de Potasio Kv1.5/antagonistas & inhibidores , Piridinas/farmacología , Descubrimiento de Drogas , Humanos , Piridinas/farmacocinética , Relación Estructura-ActividadRESUMEN
An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M(1) positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Quinolinas/química , Receptor Muscarínico M1/metabolismo , Regulación Alostérica , Animales , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Humanos , Unión Proteica , Ratas , Bibliotecas de Moléculas PequeñasRESUMEN
This letter describes the discovery of a novel series of potent Kv1.5 ion channel antagonists based on a diisopropyl amide scaffold. Structure-activity relationships of functionalized analogs are discussed. Key compound 1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea (10) exhibits significant atrial-selective effects in an in vivo model.
Asunto(s)
Acetamidas/síntesis química , Acetamidas/farmacología , Canal de Potasio Kv1.5/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Urea/análogos & derivados , Animales , Perros , Estereoisomerismo , Relación Estructura-Actividad , Factores de Tiempo , Urea/síntesis química , Urea/farmacologíaRESUMEN
[reaction: see text] Diverse organometallic reagents readily add to enantiopure N-sulfinyl beta-amino Weinreb amides providing the corresponding, stable, N-sulfinyl beta-amino carbonyl compounds in good to excellent yields. This new methodology represents a general solution to the problem of beta-amino carbonyl syntheses, which are important chiral building blocks and constituents of natural products. N-Sulfinyl beta-amino Weinreb amides are prepared by reaction of the potassium enolate of N-methoxy N-methylacetamide with sulfinimines (N-sulfinyl imines) or lithium N,O-dimethylhydroxylamine with N-sulfinyl beta-amino esters.
Asunto(s)
Aldehídos/síntesis química , Amidas/química , Cetonas/síntesis química , Sulfóxidos/química , Amidas/síntesis química , Conformación Molecular , EstereoisomerismoRESUMEN
[reaction: see text] N-Sulfinyl beta-amino Weinreb amides are prepared by condensation of sulfinimines with the potassium enolate of N-methoxy-N-methylacetamide. These new chiral building blocks are useful for the asymmetric synthesis of beta-amino carbonyl compounds, as illustrated here by the concise enantioselective syntheses of sedum alkaloids (+)-sedridine and (-)-allosedridine.