Discovery of Nivasorexant (ACT-539313): The First Selective Orexin-1 Receptor Antagonist (SO1RA) Investigated in Clinical Trials.

The orexin system consists of two neuropeptides (orexins A and B) and two receptors (OX1 and OX2). Selective OX1 receptor antagonists (SO1RA) are gaining interest for their potential use in the treatment of CNS disorders, including substance abuse, eating, obsessive compulsive, or anxiety disorders. While blocking OX2 reduces wakefulness, the expected advantage of selectively antagonizing OX1 is the ability to achieve clinical efficacy without the promotion of sleep. Herein we report our discovery efforts starting from a dual orexin receptor antagonist and describe a serendipitous finding that triggered a medicinal chemistry program that culminated in the identification of the potent SO1RA ACT-539313. Efficacy in a rat model of schedule-induced polydipsia supported the decision to select the compound as a preclinical candidate. Nivasorexant (20) represents the first SO1RA to enter clinical development and completed a first proof of concept phase II clinical trial in binge eating disorder in 2022.

Pyrazole derivatives as selective orexin-2 receptor antagonists (2-SORA): synthesis, structure-activity-relationship, and sleep-promoting properties in rats.

Selective orexin 2 receptor antagonists (2-SORA) such as seltorexant (15) are in clinical development for the treatment of insomnia and other conditions such as depression. Herein, we report our structure-activity-relationship (SAR) optimization efforts starting from an HTS hit (1) (N-(1-((5-acetylfuran-2-yl)methyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide) that was derived from an unrelated in-house GPCR-agonist program. Medicinal chemistry efforts focused on the optimization of orexin 2 receptor (OX2R) antagonistic activity, stability in liver microsomes, time dependent CYP3A4 inhibition, and aqueous solubility. Compounds were assessed for their brain-penetrating potential in in vivo experiments to select the most promising compounds for our in vivo sleep model. Our lead optimization efforts led to the discovery of the potent, brain penetrating and orally active, 2-SORA (N-(1-(2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide) 43 with efficacy in a sleep model in rats comparable to 15.

Design of Dual EP2/EP4 Antagonists through Scaffold Merging of Selective Inhibitors.

Prostaglandin E2 (PGE2) plays a key role in various stages of cancer. PGE2 signals through the EP2 and the EP4 receptors, promoting tumorigenesis, metastasis, and/or immune suppression. Dual inhibition of both the EP2 and the EP4 receptors has the potential to counteract the effect of PGE2 and to result in antitumor efficacy. We herein disclose for the first time the structure of dual EP2/EP4 antagonists. By merging the scaffolds of EP2 selective and EP4 selective inhibitors, we generated a new chemical series of compounds blocking both receptors with comparable potency. In vitro and in vivo profiling suggests that the newly identified compounds are promising lead structures for further development into dual EP2/EP4 antagonists for use in cancer therapy.

European Medicinal Chemistry Leaders in Industry (EMCL) - On the Status and Future of Medicinal Chemistry Research in Europe.

The status of industrial Medicinal Chemistry was discussed with European Medicinal Chemistry Leaders from large to mid-sized pharma and CRO companies as well as biotechs. The chemical modality space has expanded recently from small molecules to address new challenging targets. Besides the classical SAR/SPR optimization of drug molecules also their 'greenness' has increasing importance. The entire pharma discovery ecosystem has developed significantly. Beyond pharma and academia new key players such as Biotech and integrated CROs as well as Digital companies have appeared and are now to a large extend fueled by VC money. Digitalization is happening everywhere but surprisingly did not change speed and success rates of projects so far. Future Medicinal Chemists will still have to be excellent synthetic chemists but in addition they must be knowledgeable in new computational areas such as data sciences. Their ability to collaborate and to work in teams is key.

Design, Synthesis, and Optimization of Indole Acetic Acid Derivatives as Potent and Selective CRTH2 Receptor Antagonists: Discovery of ACT-774312.

Herein we report the structure-activity relationship (SAR) studies and optimization of new highly potent and selective CRTH2 receptor antagonists as potential follow-ups of our previous reported clinical candidate setipiprant (ACT-129968) for the treatment of respiratory diseases. Structural modification of the amide part of setipiprant (ACT-129968) led to the identification of the tetrahydrocarbazole derivative (S)-B-1 (ACT-453859) ((S)-2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetic acid). This compound which displayed a substantial improvement in potency in the presence of plasma versus setipiprant (ACT-129968) has exhibited an excellent overall pharmacokinetic profile. Further lead optimization to overcome a safety issue as observed in non-clinical studies with (S)-B-1 (ACT-453859), led to the discovery of the 4-azaindole derivative (S)-72 (ACT-774312) ((S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid) which was selected as a potential follow-up of setipiprant (ACT-129968).

CYP3A4 Catalyzes the Rearrangement of the Dual Orexin Receptor Antagonist Daridorexant to 4-Hydroxypiperidinol Metabolites.

The dual orexin receptor antagonist daridorexant was approved in 2022 in the USA and EU for the treatment of insomnia. The purpose of this study was the identification of its metabolic pathways and the human cytochrome P450 (P450) enzymes involved in its biotransformation. With human liver microsomes, daridorexant underwent hydroxylation at the methyl group of the benzimidazole moiety, oxidative O-demethylation of the anisole to the corresponding phenol, and hydroxylation to a 4-hydroxy piperidinol derivative. While the chemical structures of the benzylic alcohol and the phenol proved to be products of standard P450 reactions, 1D and 2D NMR data of the latter hydroxylation product was incompatible with the initially postulated hydroxylation of the pyrrolidine ring and suggested the disappearance of the pyrrolidine ring and formation of a new 6-membered ring. Its formation is best explained by initial hydroxylation of the pyrrolidine ring in 5-position to yield a cyclic hemiaminal. Hydrolytic ring opening then results in an aldehyde that subsequently cyclizes onto one of the benzimidazole nitrogen atoms to yield the final 4-hydroxy piperidinol. The proposed mechanism was substantiated using an N-methylated analogue, which might hydrolyze to the open-chain aldehyde but cannot undergo the final cyclization step. CYP3A4 was the major P450 enzyme responsible for daridorexant metabolism, accounting for 89 % of metabolic turnover.

Our Exciting Journey to ACT-451840.

We describe our work resulting in the selection of ACT-451840 ( 38 ) as a novel antimalarial drug with a novel mode of action. The compound was broadly characterized in vitro as well as in vivo in rat PK experiments as well as two different mouse malaria models. In the P. berghei infected mouse model cure could be achieved at oral doses of 300 mg/kg over 3 consecutive days. ACT-451840 was clinically investigated up to an experimental human malaria infection model, where therapeutic effects could be shown.

The Quest for the Best Dual Orexin Receptor Antagonist (Daridorexant) for the Treatment of Insomnia Disorders.

Since its discovery in 1998, the orexin system has been of interest to the research community as a potential therapeutic target for the treatment of sleep/wake disorders, stress and anxiety disorders, addiction or eating disorders. It consists of two G protein-coupled receptors, the orexin 1 and orexin 2 receptors, and two neuropeptides with agonistic effects, the orexin A and orexin B peptides. Herein we describe our efforts leading to the identification of a promising set of dual orexin receptor antagonists (DORAs) which subsequently went through physiology-based pharmacokinetic and pharmacodynamic modelling>[1] and finally led to the selection of daridorexant, currently in phase 3 clinical trials for the treatment of insomnia disorders.

20 Years of Medicinal Chemistry - Always Look at the Bright Side (of Life).

This paper summarizes a personal perspective on key learnings from projects the author was involved in over the last 20 years. For example, the discovery of macitentan, the most successful molecule to date from this personal collection, marketed by J&J for the treatment of pulmonary arterial hypertension (PAH). [1] Then the discovery of ACT-462206, a dual orexin receptor antagonist for the treatment of insomnia disorder with a serendipitously short story from the screening hit to the drug [2] followed by the identification of daridorexant, another dual orexin receptor antagonist. Daridorexant successfully passed first pivotal phase 3 clinical trial in April 2020 for the treatment of insomnia disorder [3] ("Good things come to those who wait"). Finally, ACT-451840, an antimalarial drug with a novel mechanism of action, identified in the perfect collaboration between academia and industry. The compound is in phase 2 clinical development. [4] In addition, the importance of the screening compound collection is briefly discussed, as a key asset for drug discovery. The measures Idorsia implemented to obtain valuable hits from high-throughput screening (HTS) campaigns are elaborated. [5] Drug discovery is a multi-disciplinary business with unlimited exciting challenges asking for excessive optimism when tackling them in a playful manner.

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in†vivo Efficacy in Dogs.

The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone (6), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone (42), a DORA with improved in vivo efficacy compared to 6.

Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure-Activity Relationships, and Sleep-Promoting Properties in Rats.

The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone (3), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone (51), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.

Metabolism of the Dual Orexin Receptor Antagonist ACT-541468, Based on Microtracer/ Accelerator Mass Spectrometry.

BACKGROUND: As part of an integrated and innovative approach to accelerate the clinical development of the dual receptor antagonist ACT-541468, 6 healthy subjects in one cohort in a first-in-humans (FIH) study received an oral dose of 50 mg non-labeled ACT-541468 together with a microtracer amount of 250 nCi of 14C-labeled ACT- 541468 to investigate its absorption, distribution, metabolism, and excretion (ADME). METHODS: Using accelerator mass spectrometry (AMS), radiochromatograms were constructed for fractionated plasma, urine, and feces samples. Subsequently, the structures of the metabolites were elucidated using high performance liquid chromatography (HPLC) coupled with high resolution mass spectrometry. RESULTS: In total 77 metabolites have been identified of which 30, 28, and 60 were present in plasma, urine, and feces, respectively. In plasma, the major metabolites were the mono-oxidized benzylic alcohol M3, the ACT-541468 aldehyde M1, formed by further oxidation of M3 in the benzylic position, and the doubly oxidized M10, formed by (1) benzylic oxidation of M3 (loss of one molecule of water and one molecule of ammonia) and (2) additional loss of water from the oxidized pyrrolidine ring of M5. Transformation of the pyrrolidine to a 6-membered ring was detected. Metabolites that accounted for more than 5% of total radioactivity in excreta were M2, which is also formed by oxidation at the benzylic position, M4, formed by demethylation of the methoxy-group, M7 and A6, both formed by oxidation of M4, and M10, the only major metabolite detected in urine. CONCLUSION: In conclusion, ACT-541468 is extensively metabolized predominantly by oxidative transformations.

The Screening Compound Collection: A Key Asset for Drug Discovery.

In this case study on an essential instrument of modern drug discovery, we summarize our successful efforts in the last four years toward enhancing the Actelion screening compound collection. A key organizational step was the establishment of the Compound Library Committee (CLC) in September 2013. This cross-functional team consisting of computational scientists, medicinal chemists and a biologist was endowed with a significant annual budget for regular new compound purchases. Based on an initial library analysis performed in 2013, the CLC developed a New Library Strategy. The established continuous library turn-over mode, and the screening library size of 300'000 compounds were maintained, while the structural library quality was increased. This was achieved by shifting the selection criteria from 'druglike' to 'leadlike' structures, enriching for non-flat structures, aiming for compound novelty, and increasing the ratio of higher cost 'Premium Compounds'. Novel chemical space was gained by adding natural compounds, macrocycles, designed and focused libraries to the collection, and through mutual exchanges of proprietary compounds with agrochemical companies. A comparative analysis in 2016 provided evidence for the positive impact of these measures. Screening the improved library has provided several highly promising hits, including a macrocyclic compound, that are currently followed up in different Hit-to-Lead and Lead Optimization programs. It is important to state that the goal of the CLC was not to achieve higher HTS hit rates, but to increase the chances of identified hits to serve as the basis of successful early drug discovery programs. The experience gathered so far legitimates the New Library Strategy.

The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468.

The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX1 and OX2) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.

Orexin research: patent news from 2016.

INTRODUCTION: The orexin system consists of two G-protein-coupled receptors, orexin 1 and orexin 2 and two endogenous ligands, orexin A and orexin B . It is evolutionarily highly conserved. It is involved in the promotion of wakefulness as well as in anxiety and addictive disorders. In addition, its activation via the Ox1 receptor triggers apoptosis in several cancer cell lines. Dual orexin receptor antagonists are successfully used to treat primary insomnia. The major open questions are now related to the clinical validation of Ox1 selective antagonists. A strong rationale exists for orexin agonism in the treatment of narcolepsy with cataplexy. Areas covered: The patent applications from Thomson Reuters Integrity Database added in 2016 are summarized and discussed together with the most important findings published in the scientific literature. Expert opinion: The large number of patents shows the continuing interest in the orexin receptors as targets. The structural scope covered is narrow. Questions about novelty and inventiveness are evident. The additional information published on X-ray structures on both orexin receptors opens new ways of optimizing antagonists. It might also influence the efforts in the identification of orexin receptor agonists. Being potential treatments for narcolepsy with cataplexy.

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study.

Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action.

More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy.

Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold-Hopping Approach.

Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold-hopping approach. Structure-activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time-dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P-glycoprotein (Pgp)-mediated efflux. Compound 80 c [{(1S,6R)-3-(6,7-difluoroquinoxalin-2-yl)-3,8-diazabicyclo[4.2.0]octan-8-yl}(4-methyl-[1,1'-biphenyl]-2-yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium-release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep-promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant.

From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective.

The endothelin peptides bind to two receptors found on cells of vasculature and in tissues. While the endothelin-A (ETA)-receptor is predominantly expressed in vascular smooth muscle cells, the endothelin-B (ETB)-receptor is also found in endothelial cells, fibroblasts, and neuronal cells. Activation of the endothelin system plays a driving role in several chronic cardiovascular diseases and several endothelin receptor antagonists (ERAs) (bosentan (6), ambrisentan (83) and macitentan (43)) have successfully been introduced as oral treatments for the life threatening condition of pulmonary arterial hypertension (PAH). This digest highlights the medicinal chemistry of the pyrimidine based ERAs 6 and 43 and describes the story that started with bosentan and culminated in macitentan (43). A condensed overview of the competitive landscape in the field of ERAs puts the different strategies and tactics applied by the medicinal chemists involved in this endeavor into perspective.

Substituted cyclopentanes, tetrahydrofurans and pyrrolidines as orexin-1-receptor antagonists for treatment of various CNS disorders (WO2015/055994; WO2015/124932; WO2015/124934).

The three patent applications WO2015/055994, WO2015/124932 and WO2015/124934 from Takeda Pharmaceuticals describe antagonists for the orexin-1 receptor, based on saturated substituted five-membered carbo- or heterocycles. According to the patent applications, the compounds have utility in therapeutic areas such as schizophrenia and other psychotic disorders, anxiety or addiction disorders, among others. The patent applications together describe almost 300 examples, and for most of them activity data, determined by Fluorescence Imaging Plate Reader (FLIPR) technology on the orexin-1 as well as the orexin-2 receptor, are disclosed. Structurally, the building blocks used to prepare the compounds are reminiscent of other orexin antagonist programs recently disclosed in the literature. However, the templates used are novel in the orexin antagonist field and are probably the key feature for the selectivity of the derivatives towards the orexin-1 receptor.