Key result
Compound 25 and its phosphoramide prodrug 29 were identified as selective IKur inhibitors with robust pharmacodynamic effects and improved pharmacokinetic profiles for treating atrial fibrillation.
Optimization of a phenyl quinazoline series led to the identification of a selective IKur inhibitor clinical candidate and its prodrug with favorable pharmacokinetic and pharmacodynamic profiles for the potential treatment of atrial fibrillation.
Represents a strictly preclinical step toward novel rhythm control in AF; leaves open.
current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.
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Gunaga et al. (2017) studied Atrial Fibrillation. Compound 25 and prodrug 29 was evaluated. Compound 25 and its phosphoramide prodrug 29 were identified as selective IKur inhibitors with robust pharmacodynamic effects and improved pharmacokinetic profiles for treating atrial fibrillation.
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