An Innovation 10 Years in the Making: The Stories in the Pages of ACS Medicinal Chemistry Letters.

Innovation in medicinal chemistry has been at the heart of ACS Medicinal Chemistry Letters since the journal's founding 10 years ago. In his inaugural editorial, Editor-in-Chief Dennis Liotta laid out a vision for the journal to become the "premier international journal for rapid communication of cutting-edge studies," and, after 10 years, it has become exactly that. The great hope of drug discovery scientists is that their innovations will lead to new therapeutics to treat unmet medical needs. In the spirit of innovation and in celebration of the recent 10th anniversary of ACS Med. Chem. Lett., we highlight five therapeutics that were first reported or first comprehensively characterized within ACS Med. Chem. Lett.. This overview also serves to introduce the expansion of the scope of the Innovations article type to include Topical Innovations. With this extension, the journal hopes to provide a forum to showcase concise (rather than comprehensive) reviews of topics that are both timely and of great interest to the medicinal chemistry community. Moreover, these articles will emphasize the next steps to move the field toward new areas of interest in medicinal chemistry. Appropriate topics might include case studies of clinical candidates or approved drugs, new assay technologies in drug discovery, novel target classes, and innovative new approaches towards modulation of human physiology. Since its founding 10 years ago, ACS Med. Chem. Lett. has established itself as a venue for the rapid communication of studies in medicinal chemistry and drug discovery. There have been several drugs and clinical candidates that were first reported or first comprehensively characterized in ACS Med. Chem. Lett. In celebration of the 10th anniversary of ACS Med. Chem. Lett. this Topical Innovations article highlights five of these compounds: Ivosidenib, Siponimod, Glasdegib, Parsaclisib, and Dabrafenib.

Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity.

IRAK4 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent molecule 19 that achieves robust in vivo inhibition of cytokines relevant to human disease.

Inhaled Janus Kinase (JAK) inhibitors for the treatment of asthma.

Multiple asthma-relevant cytokines including IL-4, IL-5, IL-13, and TSLP depend upon JAKs for signaling. JAK inhibition may, therefore, offer a novel intervention strategy for patients with disease refractory to current standards of care. Multiple systemically delivered JAK inhibitors have been approved for human use or are under clinical evaluation in autoimmune diseases such as rheumatoid arthritis. However, the on-target side effect profiles of these agents are likely not tolerable for many asthmatic patients. Limiting JAK inhibition to the lung is expected to improve therapeutic index relative to systemic inhibition. Thus, inhaled JAK inhibitors with lung-restricted exposure are of high interest as potential treatments for asthma.

Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.

A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans. This semisaturated bicycle provided superior druglike properties while maintaining excellent potency and selectivity. Improved physicochemical properties allowed for progression into in vivo experiments, where lead molecules exhibited low clearance and showed target-based inhibition of IRAK4 signaling in an inflammation-mediated PK/PD mouse model.

Kinase Inhibitors for the Treatment of Immunological Disorders: Recent Advances.

Small molecule inhibitors targeting autoimmune and inflammatory processes have been an area of intense focus within academia and industry. Much of this work has been aimed at key kinases operating as central nodes in inflammatory signaling pathways. While this focus has led to over 30 FDA-approved small molecule kinase inhibitors, only one is currently approved for autoimmune and inflammatory diseases. Despite this lack of success, there remains tremendous reason for excitement. Our growing understanding of the biology involved in the inflammatory response, the factors that lead to safer small molecule kinase inhibitors, and the availability of selective tool molecules for interrogating specific nodes and pathways are all pushing the field forward. This article focuses on recent developments requiring novel approaches to create safe and effective small molecule kinase inhibitors and where further work is needed to realize the promise of small molecule kinase inhibitors for patient benefit.

Mechanism-Guided Development of a Highly Active Bis-thiourea Catalyst for Anion-Abstraction Catalysis.

We describe the rational design of a linked, bis-thiourea catalyst with enhanced activity relative to monomeric analogues in a representative enantioselective anion-abstraction reaction. Mechanistic insights guide development of this linking strategy to favor substrate activation though the intramolecular cooperation of two thiourea subunits while avoiding nonproductive aggregation. The resulting catalyst platform overcomes many of the practical limitations that have plagued hydrogen-bond-donor catalysis and enables use of catalyst loadings as low as 0.05 mol %. Computational analyses of possible anion-binding modes provide detailed insight into the precise mechanism of anion-abstraction catalysis with this pseudo-dimeric thiourea.

Enantioselective catalytic transannular ketone-ene reactions.

Highly enantio- and diastereoselective transannular ketone-ene reactions are catalyzed by a new chromium(III) triflate tridentate Schiff base complex. Electronically unactivated keto-olefins undergo heteroene reactions at ambient temperature to afford enantioenriched bicyclic alcohols, common structural motifs in natural products. The kinetic resolution of a configurationally stable planar-chiral cyclodecenone is also described.

Enantioselective formal aza-Diels-Alder reactions of enones with cyclic imines catalyzed by primary aminothioureas.

A highly enantio- and diastereoselective synthesis of indolo- and benzoquinolizidine compounds has been developed through the formal aza-Diels-Alder reaction of enones with cyclic imines. This transformation is catalyzed by a new bifunctional primary aminothiourea that achieves simultaneous activation of both the enone and imine reaction components.

Enantioselective total synthesis of (+)-reserpine.

A catalytic, enantioselective synthesis of (+)-reserpine is reported. The route features a highly diastereoselective, chiral catalyst-controlled formal aza-Diels-Alder reaction between a 6-methoxytryptamine-derived dihydro-ß-carboline and an enantioenriched α-substituted enone to form a key tetracyclic intermediate. This approach addresses the challenge of setting the C3 stereogenic center by using catalyst control. Elaboration of the tetracycle to (+)-reserpine includes an intramolecular aldol cyclization and a highly diastereoselective hydrogenation of a sterically hindered enoate.

Dinuclear zinc-catalyzed asymmetric desymmetrization of acyclic 2-substituted-1,3-propanediols: a powerful entry into chiral building blocks.

The asymmetric acylation of meso-2-substituted-1,3-propanediols by using an amphoteric chiral dinuclear zinc catalyst is described. It is has been demonstrated that both 2-alkyl- and 2-aryl-1,3-propanediols can be desymmetrized in high yields and enantioselectivities by using the same family of ligands. Given that both antipodes of the chiral catalyst are available, both enantiomers of the desymmetrized product can be obtained from the same starting material. The synthetic utility of the desymmetrized products has been demonstrated by the synthesis of several chiral building blocks with high enantiomeric purities.