Discovery of 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a PotentI_KurInhibitor

Abstract

A new series of phenylquinazoline inhibitors of K v 1.5 is disclosed. The series was optimized for K v 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)-quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

“…The 5-phenyl- N -(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)­quinazolin-4-amine 14 is a potent I Kur current blocker that is a potentially safe agent for the maintenance of normal sinus rhythm. However, compound 14 with high brain exposure had the potential for CNS side effects . After the transformation of the introduction of hydrogen bond donors, Finlay and co-workers discovered compound 15 with low brain exposure while maintaining the in vitro potency and selectivity profile of the I Kur current blocker (Figure ).…”

“…However, compound 14 with high brain exposure had the potential for CNS side effects. 91 After the transformation of the introduction of hydrogen bond donors, Finlay and co-workers discovered compound 15 with low brain exposure while maintaining the in vitro potency and selectivity profile of the I Kur current blocker (Figure 7). 92 In the past five years, many medicinal chemists have used HBD removal to improve BBB penetration.…”

Selective IKur 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

“…7 Thus, compounds that selectively inhibit I Kur are expected to have a low potential for ventricular proarrhythmia along with an improved safety profile. 8−11 Our recent disclosure 12 in the phenylquinazoline series details the discovery of 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (1) as a potent (K V 1.5; IC 50 = 90 nM) and selective I Kur inhibitor that demonstrated robust effects in both rat and rabbit pharmacodynamic models (Figure 1). However, a high brain to plasma ratio (B/P) of 2.8, with the potential for central nervous system (CNS) side effects, blocked the progress of this compound.…”

“…The permeability of molecules across the blood−brain barrier is determined by physicochemical properties such as size, polar surface area, lipophilicity, hydrogen bonding potential, charge, and conformation. 13 Compounds in the phenylquinazoline series had high levels of plasma protein binding 12 in rat and human in addition to low solubility at pH 7.4, which led to recovery issues in the high-throughput PAMPA and Caco permeability assays. Therefore, the in vitro permeability or efflux data could not be routinely used for SAR development or assessment of P-gp efflux.…”

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

“…Based on the structure of MK-0448, a cluster of derivatives were synthesized and tested the Kv1.5 inhibitory effect and in vivo and in vitro toxicity. MK-1832 (94) was considered to be the Finlay and co-workers [103] explored phenylquinazoline derivatives as Kv1.5 inhibitors. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (90) was identified as a potent and ion channel selective inhibitor (Kv1.5 IC50: 90 nM, hERG inhibition: 43% at 10 μM) with robust efficacy in the pre-clinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model ( Figure 28).…”