Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics.

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.

Parallel synthesis of N-biaryl quinolone carboxylic acids as selective M(1) positive allosteric modulators.

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.

N-sulfinyl beta-amino Weinreb amides: synthesis of enantiopure beta-amino carbonyl compounds. Asymmetric synthesis of (+)-sedridine and (-)-allosedridine.

[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.

Potent antagonists of the Kv1.5 potassium channel: synthesis and evaluation of analogous N,N-diisopropyl-2-(pyridine-3-yl)acetamides.

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.

Asymmetric synthesis of beta-amino carbonyl compounds with N-sulfinyl beta-amino Weinreb amides.

[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.