Conspectus Atropisomerism is a conformational chirality that occurs when there is hindered rotation about a σ-bond. While atropisomerism is exemplified by biaryls, it is observed in many other pharmaceutically relevant scaffolds including heterobiaryls, benzamides, diarylamines, and anilides. As bond rotation leads to racemization, atropisomers span the gamut of stereochemical stability. LaPlante has classified atropisomers based on their half-life of racemization at 37 °C: class 1 (t1/2 < 60 s), class 2 (60 s < t1/2 < 4.5 years), and class 3 (t1/2 > 4.5 years). In general, class-3 atropisomers are considered to be suitable for drug development. There are currently four FDA-approved drugs that exist as stable atropisomers, and many others are in clinical trials or have recently appeared in the drug discovery literature. Class-1 atropisomers are more prevalent, with ∼30% of recent FDA-approved small molecules possessing at least one class-1 axis. While class-1 atropisomers do not possess the requisite stereochemical stability to meet the classical definition of atropisomerism, they often bind a given target in a specific set of chiral conformations. Over the past decade, our laboratory has embarked on a research program aimed at leveraging atropisomerism as a design feature to improve the target selectivity of promiscuous lead compounds. Our studies initially focused on introducing class-3 atropisomerism into promiscuous kinase inhibitors, resulting in a proof of principle in which the different atropisomers of a compound can have different selectivity profiles with potentially improved target selectivity. This inspired a careful analysis of the binding conformations of diverse ligands bound to different target proteins, resulting in the realization that the sampled dihedral conformations about a prospective atropisomeric axis played a key role in target binding and that preorganizing the prospective atropisomeric axis into a desired target’s preferred conformational range can lead to large gains in target selectivity. As atropisomerism is becoming more prevalent in modern drug discovery, there is an increasing need for strategies for atropisomerically pure samples of pharmaceutical compounds. This has led us and other groups to develop catalytic atroposelective methodologies toward pharmaceutically privileged scaffolds. Our laboratory has contributed examples of atroposelective methodologies toward heterobiaryl systems while also exploring the chirality of less-studied atropisomers such as diarylamines and related scaffolds. This Account will detail recent encounters with atropisomerism in medicinal chemistry and how atropisomerism has transitioned from a “lurking menace” into a leverageable design strategy in order to modulate various properties of biologically active small molecules. This Account will also discuss recent advances in atroposelective synthesis, with a focus on methodologies toward pharmaceutically privileged scaffolds. We predict that a better understanding of the effects of conformational restriction about a prospective atropisomeric axis on target binding will empower chemists to rapidly “program” the selectivity of a lead molecule toward a desired target.

https://pubs.acs.org/doi/pdf/10.1021/acs.accounts.2c00500

Atropisomerism in the Pharmaceutically Relevant Realm

Introduction: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a central role in regulating cell growth and proliferation and...

Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016–2020)

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.

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

Protein kinases are key regulators of cellular signaling and play a critical role in oncogenesis. Inhibitors of protein kinases are pursued by both industry and academia as a promising target for cancer therapy. Within the protein kinases, the ATP site has produced more than 40 FDA‐approved drugs. The ATP site is broadly composed of a hinge region, gatekeeper residues, DFG‐loop, ribose pocket, and other hydrophobic regions. The hinge region in the ATP site can be used for designing potent inhibitors. In this review, we discuss some representative studies that will highlight the interactions of heterocyclic compounds with hinge regions of different kinases like BRAF kinase, EGRF kinase, MAP kinase, and Mps1 kinase.

Designing of kinase hinge binders: A medicinal chemistry perspective

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions.

A series of PI3Kβ selective inhibitors derived from a novel 4-(1H-benzo[d]imidazol-1-yl)quinoline chemotype has been rationally designed. Crucial to achieving the desired selectivity over the other class I PI3K isoforms, including the challenging δ-isoform, was the identification of a subset of substituted pyridine hinge binders. This work led to the discovery of (P)-14, a highly selective and orally bioavailable PI3Kβ inhibitor displaying an excellent pharmacokinetic profile in addition to great cellular potency in various PTEN-deficient tumor cell lines. Results from a dog toxicology study revealing structure-related, off-target ocular toxicity are also briefly discussed.

Fatima Arjmand

Papers

Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif