Synthesis and in vitro evaluation of derivatives of the β1-adrenergic receptor antagonist HX-CH 44

Isopropyl- and fluoroisopropyl-amino derivatives of the β1-adrenergic receptor antagonist 2-[4-[3-(tert-butyl-amino)-2-hydroxypropoxy]phenyl]-3-methyl-6-methoxy-4(3H)-quinazolinone ((±)HX-CH 44) were synthesized, including a concise and efficient preparation of the core, 2-(4-hydroxyphenyl)-6-methoxy-3-methylquinazolin-4(3H)-one. In vitro binding assays showed that the fluorinated analog was selective towards β1-adrenergic receptors over β2-adrenergic and 5-HT1A receptors. An X-ray crystallographic characterization of the fluorinated analog is also reported.