Medicinal Chemistry Profiling of Monocyclic 1,2-Azaborines.
The first examples of biologically active monocyclic 1,2-azaborines have been synthesized and demonstrated to exhibit not only improved in vitro aqueous solubility in comparison with their corresponding carbonaceous analogues, but in the context of a CDK2 inhibitor, also improved biological activity and better in vivo oral bioavailability. This proof-of-concept study establishes the viability of monocyclic 1,2-azaborines as a novel pharmacophore with distinct pharmacological profiles that can help address challenges associated with solubility in drug development research.
Department of Chemistry, Boston College, Chestnut Hill, MA, 02467, USA.
Peng
P
Zhao
Novartis Institutes for Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA.
David O
DO
Nettleton
Novartis Institutes for Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA.
Rajeshri G
RG
Karki
Novartis Institutes for Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA.
Frédéric J
FJ
Zécri
Department of Chemistry, Boston College, Chestnut Hill, MA, 02467, USA.
Shih-Yuan
SY
Liu
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001896:Boron Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D006860:Hydrogen Bonding; D008297:Male; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
C556261:1,2-azaborine; D001896:Boron Compounds; D047428:Protein Kinase Inhibitors; D051357:Cyclin-Dependent Kinase 2
BN heterocycle; CDK2 inhibitors; azaborines; drug discovery; solubility