Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3-Kinase (PI3K) β Inhibitor

Abstract

Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive ( M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active ( P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kβ inhibitor.

Racemisation in Chemistry and Biology

“…[15,54] Calculationso n1 using the MMFF force field and at the B3LYP/6-31G** level complemented variabletemperature NMR measurements that suggestabarrier to rotation of 35 kcal mol À1 . [22] Removal of the methyl on the imidazole ring was computed to lower the barrier to about 17 kcal mol À1 consistentw ith the observation of free rotation. Another combined experimental and computational study of 21 and 22 revealed the significant effect of ring expansion on racemisation rate (Table 3).…”

“…Compounds with barriers at the HF/6‐31G** level below about 20 kcal mol −1 or above approximately 30 kcal mol −1 can be developed as single compounds, whereas those in between these two extremes are likely to form mixtures with a time dependence that is comparable to storage and dosing of drugs . Variations on this approach have been described subsequently …”

“…This type of racemisation is intimately related to atropisomerism and has been studied computationally . Calculations on 1 using the MMFF force field and at the B3LYP/6‐31G** level complemented variable‐temperature NMR measurements that suggest a barrier to rotation of 35 kcal mol −1 . Removal of the methyl on the imidazole ring was computed to lower the barrier to about 17 kcal mol −1 consistent with the observation of free rotation.…”

“…NMR can also be used to monitor racemisation by the addition of a chiral shift reagent to provide differentiation between enantiomers, as long as the chiral shift reagent does not affect the racemisation reaction. Variable‐temperature NMR experiments can be used to study atropisomerism and racemisation of chiral axes …”

“…The differences in properties extend to those molecules that contain chiral axes instead of stereogenic centres. In a recent report, the P atropisomer of the phosphoinositide 3‐kinase inhibitor 1 (Figure ) was found to be a markedly better inhibitor than its enantiomeric alternative (the M atropisomer) . In addition, 1 has a lower in vitro clearance than its enantiomer in tests using human hepatocytes or microsomes; its enantiomer is particularly liable to metabolism by aldehyde oxidase.…”