ABSTRACT
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.
Subject(s)
Kv1.5 Potassium Channel/antagonists & inhibitors , Pyridines/pharmacology , Drug Discovery , Humans , Pyridines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Carboxylic Acids/chemical synthesis , Quinolines/chemistry , Receptor, Muscarinic M1/metabolism , Allosteric Regulation , Animals , Blood Proteins/chemistry , Blood Proteins/metabolism , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Humans , Protein Binding , Rats , Small Molecule LibrariesABSTRACT
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.
Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Kv1.5 Potassium Channel/antagonists & inhibitors , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Urea/analogs & derivatives , Animals , Dogs , Stereoisomerism , Structure-Activity Relationship , Time Factors , Urea/chemical synthesis , Urea/pharmacologyABSTRACT
[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.
Subject(s)
Aldehydes/chemical synthesis , Amides/chemistry , Ketones/chemical synthesis , Sulfoxides/chemistry , Amides/chemical synthesis , Molecular Conformation , StereoisomerismABSTRACT
[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.
