Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [79]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, prepro-orexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [120, 79]. Orexin signaling has been associated with regulation of sleep and wakefulness, reward and addiction, appetite and feeding, pain gating, stress response, anxiety and depression. Currently the orexin receptor ligands in clinical use are the dual orexin receptor antagonists suvorexant, lemborexant and daridorexant, which are used as hypnotics, and several dual, as well as OX1- and OX2-selective antagonists are under development for different indications. Multiple orexin agonists are in development for the treatment of narcolepsy and other sleep disorders. Orexin receptor 3D structures have been solved [150, 148, 55, 130, 47, 113, 7, 149].

Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Nav1.8 sodium channel. Parallel library synthesis, guided by in silico predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay. Progress toward the lead identification, optimization, and in vivo efficacy of these compounds will be discussed.

Virtual screening was leveraged to identify novel series of histone deacetylase 6 (HDAC6) inhibitors prior to conducting a high-throughput screen. The virtual screen was designed to augment and expand on chemical matter that would otherwise be unavailable for high-throughput screening. Through this effort we succeeded in identifying four novel, potent and highly selective HDAC6 inhibitor series. These series displayed favorable ligand binding efficiencies and good potential for further optimization. The virtual design specifications and results are discussed herein.

PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.

Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [43]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [117]. Orexin signaling has been associated with regulation of sleep and wakefulness, reward and addiction, appetite and feeding, pain gating, stress response, anxiety and depression. Currently the orexin receptor ligands in clinical use are the dual orexin receptor antagonists suvorexant and lemborexant and daridorexant, which are used as hypnotics, and several dual and OX2-selective antagonists are under development. Multiple orexin agonists are in development for the treatment of narcolepsy and other sleep disorders. Orexin receptor 3D structures have been solved [146, 144, 55, 126, 47, 109, 7, 145].

A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors.

High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.

The development of therapeutics for central nervous system (CNS) disorders has many challenges that result in low probability of success and longer-than-typical development timelines. Suvorexant (Belsomra), the first dual orexin receptor antagonist used for insomnia, was approved by the United States Food and Drug Administration ∼10 years after the initial high-throughput screen was conducted to identify orexin receptor antagonists. What accounted for this success and speed? Here we suggest that this program was unique and set up for success by (1) having a robust and high-throughput pharmacodynamic readout that was translatable across species, including humans, (2) a well-validated target with a defined product profile, resulting in a highly energized team with a can-do attitude, and (3) a highly executable and streamlined clinical strategy. The utility of Belsomra for insomnia, as well as other neurological and psychiatric diseases, continues to be explored, most recently for insomnia associated with Alzheimer's disease.

Innovations in synthetic chemistry have enabled the discovery of many breakthrough therapies that have improved human health over the past century. In the face of increasing challenges in the pharmaceutical sector, continued innovation in chemistry is required to drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock access to previously unattainable chemical matter, but also inspire new concepts as to how we design and build chemical matter. We identify some of the most important recent advances in synthetic chemistry as well as opportunities at the interface with partner disciplines that are poised to transform the practice of drug discovery and development.

The JETSCAPE Collaboration has recently announced the first release of the JETSCAPE package that provides a modular, flexible, and extensible Monte Carlo event generator. This innovative framework makes it possible to perform a comprehensive study of multi-stage high-energy jet evolution in the Quark-Gluon Plasma. In this work, we illustrate the performance of the event generator for different algorithmic approaches to jet energy loss, and reproduce the measurements of several jet and hadron observables as well as correlations between the hard and soft sector. We also carry out direct comparisons between different approaches to energy loss to study their sensitivity to those observables.

The JETSCAPE simulation framework is an overarching computational envelope for developing complete event generators for heavy-ion collisions. It allows for modular incorporation of a wide variety of existing and future software that simulates different aspects of a heavy-ion collision. The default JETSCAPE package contains both the framework, and an entire set of indigenous and third party routines that can be used to directly compare with experimental data. In this article, we outline the algorithmic design of the JETSCAPE framework, define the interfaces and describe the default modules required to carry out full simulations of heavy-ion collisions within this package. We begin with a description of the various physics elements required to simulate an entire event in a heavy-ion collision, and distribute these within a flowchart representing the event generator and statistical routines for comparison with data. This is followed by a description of the abstract class structure, with associated members and functions required for this flowchart to work. We then define the interface that will be required for external users of JETSCAPE to incorporate their code within this framework and to modify existing elements within the default distribution. We conclude with a discussion of some of the physics output for both $p$-$p$ and $A$-$A$ collisions from the default distribution, and an outlook towards future releases. In the appendix, we discuss various architectures on which this code can be run and outline our benchmarks on similar hardware.

The modification of jet substructure in relativistic heavy-ion collisions is studied using JETSCAPE, a publicly available software package containing a framework for Monte Carlo event generators. Multi-stage jet evolution in JETSCAPE provides an integrated description of jet quenching by combining multiple models, with each becoming active at a different stage of the parton shower evolution. Jet substructure modification due to different aspects of jet quenching is studied using jet shape and jet fragmentation observables. Various combinations of jet energy loss models are exploed, with medium background provided by (2 + 1)-D VISHNU with TRENTo+freestreaming initial conditions. Results reported here are from simulations performed within JETSCAPE framework.

Innovations in synthetic chemistry have enabled the discovery of many breakthrough therapies that have improved human health over the past century. In the face of increasing challenges in the pharmaceutical sector, continued innovation in chemistry is required to drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock access to previously unattainable chemical matter, but also inspire new concepts as to how we design and build chemical matter. We identify some of the most important recent advances in synthetic chemistry as well as opportunities at the interface with partner disciplines that are poised to transform the practice of drug discovery and development.

The DarkLight collaboration proposes a run of 1000 hours (45 days) at the CEBAF injector (45 MeV beam with 150 μA current) to search in the e+e− invariant mass region around 17 MeV in electron scattering from tantalum for evidence of new physics, motivated by anomalies resulting from the muon g − 2 determination and reported in the decays of 8Be. The proposed experiment is a unique search for a low-mass mediator between the Standard Model and the dark sector in a coupling-mass region of great current interest. The experiment can form the basis for M.S. and Ph.D. theses for graduate students at Hampton University, MIT and Stony Brook University.

HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.

Chronic insomnia is defined as a persistent difficulty with sleep initiation maintenance or non-restorative sleep. The therapeutic standard of care for this condition is treatment with gamma-aminobutyric acid (GABA)A receptor modulators, which promote sleep but are associated with a panoply of side effects, including cognitive and memory impairment. Dual orexin receptor antagonists (DORAs) have recently emerged as an alternative therapeutic approach that acts via a distinct and more selective wake-attenuating mechanism with the potential to be associated with milder side effects. Given their distinct mechanism of action, the current work tested the hypothesis that DORAs and GABAA receptor modulators differentially regulate neurochemical pathways associated with differences in sleep architecture and cognitive performance induced by these pharmacological mechanisms. Our findings showed that DORA-22 suppresses the release of the wake neurotransmitter histamine in the lateral hypothalamus, prefrontal cortex, and hippocampus with no significant alterations in acetylcholine levels. In contrast, eszopiclone, commonly used as a GABAA modulator, inhibited acetylcholine secretion across brain regions with variable effects on histamine release depending on the extent of wakefulness induction. In normal waking rats, eszopiclone only transiently suppressed histamine secretion, whereas this suppression was more obvious under caffeine-induced wakefulness. Compared with the GABAA modulator eszopiclone, DORA-22 elicits a neurotransmitter profile consistent with wake reduction that does not impinge on neurotransmitter levels associated with cognition and rapid eye movement sleep.

Orexin receptor (OX1R, OX2R) antagonism induces sleep architecture characterized by increases in both NREM and REM reminiscent of unmedicated sleep. REM sleep is thought to be controlled in part by noradrenergic neurons of the locus coeruleus (LC), a site of selective OX1R expression. This work utilizes selective DORA and 2-SORA antagonists in combination with prazosin (alpha1-noradrenergic blocker) in genetic models to determine specific roles of OX1R and OX2R in sleep architecture changes induced by DORAs and 2-SORAs. Sleep architecture was evaluated by polysomnography in preclinical animals (mice, rats, dogs, and rhesus monkeys) via radio-telemetry implants in across 3–5 days of drug administration. Stages of sleep were quantified with automated software modules evaluating ECoG, EMG, EOG (dog, monkey) data. Drug-induced sleep stage changes were correlated with receptor occupancy in transgenic rats expressing hOX2R at Cmax. A double-blind, randomized, 4-period crossover Phase I polysomnography study evaluated responses to single doses of 2-SORA, MK-1064, in twenty healthy male subjects. In rats, NREM and REM sleep induced by DORAs is statistically no different from un-medicated inactive phase sleep. Mouse genetic models indicate that OX2R primarily modulates orexin-induced arousal, while OX1R appears involved in vigilance state gating. Prazosin similarly augmented REM sleep induced by DORAs and 2-SORAs, however, indicating that noradrenergic signaling from the LC is not maximally inhibited by either treatment. In rats, sleep was induced by lower receptor occupancies of DORAs relative to 2-SORAs. Across mammals including humans, REM sleep was induced by MK-1064, a 2-SORA exhibiting 3000x binding selectivity for OX2R over OX1R. DORAs promote sleep by attenuating arousal and reducing sleep stage threshold through mechanisms beyond alpha1-noradrenergic signaling of the LC. 2-SORAs promote REM sleep across mammals in a manner similar to DORAs and do not appear to measurably differentiate from DORAs in sleep architecture. This work was funded by Merck & Co., Inc.