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

IC87114 [compound <b>1</b>, (2-((6-amino-9<i>H</i>-purin-9-yl)­methyl)-5-methyl-3-(<i>o</i>-tolyl)­quinazolin-4­(3<i>H</i>)-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(3<i>H</i>)-one nucleus to the <i>o</i>-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the a<i>S</i> and a<i>R</i> isomers of compound <b>1</b> do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium. The a<i>S</i> and a<i>R</i> atropisomers of <b>1</b> were equally active in the PI3Kδ assay. Conversely, the introduction of a methyl group at the methylene hinge connecting the 6-amino-9<i>H</i>-purin-9-yl pendant to the quinazolin-4­(3<i>H</i>)-one nucleus of both a<i>S</i> and a<i>R</i> isomers of <b>1</b> 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 <b>1</b> analogues to PI3Kδ enzyme

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

IC87114 [compound <b>1</b>, (2-((6-amino-9<i>H</i>-purin-9-yl)­methyl)-5-methyl-3-(<i>o</i>-tolyl)­quinazolin-4­(3<i>H</i>)-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(3<i>H</i>)-one nucleus to the <i>o</i>-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the a<i>S</i> and a<i>R</i> isomers of compound <b>1</b> do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium. The a<i>S</i> and a<i>R</i> atropisomers of <b>1</b> were equally active in the PI3Kδ assay. Conversely, the introduction of a methyl group at the methylene hinge connecting the 6-amino-9<i>H</i>-purin-9-yl pendant to the quinazolin-4­(3<i>H</i>)-one nucleus of both a<i>S</i> and a<i>R</i> isomers of <b>1</b> 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 <b>1</b> analogues to PI3Kδ enzyme

1,2,4-Triazolyl 5‑Azaspiro[2.4]heptanes: Lead Identification and Early Lead Optimization of a New Series of Potent and Selective Dopamine D3 Receptor Antagonists

A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]­heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases. A few derivatives with overall favorable developability characteristics were selected for further late lead optimization studies