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J Med Chem. 2017 May 25;60(10):4304-4315. doi: 10.1021/acs.jmedchem.7b00247. Epub 2017 May 15.

Atropisomerism and Conformational Equilibria: Impact on PI3Kδ Inhibition of 2-((6-Amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one (IC87114) and Its Conformationally Restricted Analogs.

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Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma , Viale delle Scienze 27/A, 43124 Parma, Italy.
Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A. , Largo F. Belloli 11/A, 43122 Parma, Italy.
Aptuit s.r.l. , Via Fleming 4, 37135 Verona, Italy.


IC87114 [compound 1, (2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one)] is a potent PI3K inhibitor selective for the δ isoform. As predicted by molecular modeling calculations, rotation around the bond connecting the quinazolin-4(3H)-one nucleus to the o-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the aS and aR isomers of compound 1 do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium. The aS and aR atropisomers of 1 were equally active in the PI3Kδ assay. Conversely, the introduction of a methyl group at the methylene hinge connecting the 6-amino-9H-purin-9-yl pendant to the quinazolin-4(3H)-one nucleus of both aS and aR isomers of 1 had a critical effect on the inhibitory activity, indicating that modulation of the conformational space accessible for the two bonds departing from the central methylene considerably affects the binding of compound 1 analogues to PI3Kδ enzyme.

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