Atropisomerism in Drug Discovery: A Medicinal Chemistry Perspective Inspired by Atropisomeric Class I PI3K Inhibitors

ConspectusAtropisomerism is a type of axial chirality resulting from hindered rotation about a σ bond that gives rise to nonsuperimposable stereoisomers (termed "atropisomers"). The inversion of chirality of an atropisomeric axis is a time- and temperature-dependent dynamic process occurring by simple bond rotation. For this reason, the rotational energy barrier (ΔErot) and the interconversion rate between an atropisomeric pair of biologically active molecules are important parameters to consider in drug discovery.Many compounds with atropisomeric axes advance into development every year. The vast majority of them have low rotational energy barriers (ΔErot lower than 20 kcal/mol), meaning they are rapidly equilibrating conformers and considered achiral (class 1 atropisomers). Compounds in class 2 (ΔErot = 20 to 30 kcal/mol) can be challenging to develop given that the stereochemical integrity of the atropisomeric axes can be compromised over time. It has been recommended that small molecule drug candidates containing one or more atropisomeric axes with rotational energy barriers greater than 30 kcal/mol (class 3 atropisomers) should be developed as single atropisomers.In medicinal chemistry, a σ bond with restricted rotation is engineered into a bioactive molecule primarily to limit its number of accessible conformations, thereby minimizing entropic and/or enthalpic energy penalties associated with biological target binding. In addition to enhanced pharmacology, potential positive outcomes of introducing atropisomerism include improved physicochemical properties and superior pharmacokinetics/ADME profiles. The application of atropisomerism in medicinal chemistry has become increasingly enabled due to recent advances in synthesis, purification, and analysis, as described in this special issue and recent review articles.Herein, we discuss two case studies from our own work in which restricting rotation about axes of atropisomerism led to significant improvements in pharmacological, physicochemical, and ADME properties for different series of PI3K inhibitors. In the first instance, a restricted axis of rotation was designed to mitigate an acid-mediated hydrolytic degradation pathway observed in a series of PI3Kδ inhibitors. The conformational constraint disrupts conjugation between a quinazolinone and a pyridine, leading to improved chemical stability under acidic conditions. In the second case study, introduction of a restricted axis of rotation between two heteroaromatic systems in a series of PI3Kβ inhibitors generated pairs of atropisomeric compounds with significantly different biological activities. Advanced profiling also demonstrated clear substrate stereospecificity in regard to metabolism by aldehyde oxidase. Gratifyingly, the eutomer (more active atropisomer) shows significantly less susceptibility for oxidative metabolism relative to the distomer (less active atropisomer). The improvements in potency, selectivity, chemical stability, and metabolic stability discussed in this manuscript are all directly related to the concept of atropisomerism.