Benzazaborinines as Novel Bioisosteric Replacements of Naphthalene: Propranolol as an Example

• Published in: Journal of medicinal chemistry Vol. 58; no. 23; pp. 9287 - 9295
• Main Authors: Rombouts, Frederik J. R, Tovar, Fulgencio, Austin, Nigel, Tresadern, Gary, Trabanco, Andrés A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.12.2015; Amer Chemical Soc
• Subjects: Adrenergic beta-Antagonists - chemistry; Adrenergic beta-Antagonists - pharmacokinetics; Adrenergic beta-Antagonists - pharmacology; Animals; Aza Compounds - chemistry; Aza Compounds - pharmacokinetics; Aza Compounds - pharmacology; Benzene Derivatives - chemistry; Benzene Derivatives - pharmacokinetics; Benzene Derivatives - pharmacology; Biological Availability; Borinic Acids - chemistry; Borinic Acids - pharmacokinetics; Borinic Acids - pharmacology; Brain - metabolism; Cell Line; Chemistry, Medicinal; CHO Cells; Cricetulus; Drug Design; Drug Stability; Humans; Life Sciences & Biomedicine; Mice; Models, Molecular; Pharmacology & Pharmacy; Propranolol - analogs & derivatives; Rats; Science & Technology; DRUG DESIGN; CHEMISTRY; CROSS-COUPLING REACTIONS; INHIBITORS; DATABASE; LIGAND DESIGN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01088

Two benzazaborinine analogues of propranolol were synthesized and extensively profiled in vitro and in vivo. These analogues showed potency and physicochemical and in vitro ADME–tox profiles comparable to propranolol. In addition, both benzazaborinine analogues showed excellent bioavailability and brain penetration following subcutaneous administration in a pharmacokinetic study in rats. These studies unveil the potential of aromatic azaborinines as bioisosteric replacements of naphthalene in drug discovery programs.