1 research outputs found
Selective <i>I</i><sub>Kur</sub> Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5‑[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide
We
have recently disclosed 5-phenyl-<i>N</i>-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)Âquinazolin-4-amine <b>1</b> as a potent <i>I</i><sub>Kur</sub> current blocker
with selectivity versus <i>h</i>ERG, Na and Ca channels,
and an acceptable preclinical PK profile. Upon further characterization <i>in vivo</i>, compound <b>1</b> 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)Âquinazolin-2-yl]Âpyridine-3-sulfonamide
(<b>25</b>) was identified as the lead compound in this series.
Compound <b>25</b> 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 <b>25</b> to mitigate pH-dependent absorption resulted in
identification of the corresponding phosphoramide prodrug (<b>29</b>) with an improved solubility and pharmacokinetic profile