Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration

SummaryMetabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases

Discovery of 1H-pyrrolo[2,3-c]pyridine-7-carboxamides as novel, allosteric mGluR5 antagonists

1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed improving the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency

Smart design of patient centric long-acting products: from preclinical to marketed pipeline trends and opportunities.

We see a development in the field of long-acting products to serve patients with chronic diseases by providing benefits in adherence, efficacy and safety of the treatment. This review investigates features of long-acting products on the market/pipeline to understand which drug substance (DS) and drug product (DP) characteristics likely enable a successful patient-centric, low-dosing frequency product.This review evaluates marketed/pipeline long-acting products with greater than one week release of small molecules and peptides by oral and injectable route of administration (RoA), with particular focus on patient centricity, adherence impact, health outcomes, market trends, and the match of DS/DP technologies which lead to market success.Emerging trends are expected to change the field of long-acting products in the upcoming years by increasing capability in engineered molecules (low solubility, long half-life, high potency, etc.), directly developing DP as long-acting oral/injectable, increasing the proportion of products for local drug delivery, and a direction towards more subcutaneous, self-administered products. Among long-acting injectable products, nanosuspensions show a superiority in dose per administration and dosing interval, overwhelming the field of infectious diseases with the recently marketed products

Distinct effects of orexin 2 receptor antagonism and dual orexin 1,2 receptor antagonism on sleep architecture in mice.

Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, SB-649868, suvorexant (MK-4305) and filorexant (MK-6096), have shown promise for the treatment of insomnias and sleep disorders. Whether antagonism of both OX1R and OX2R is necessary for sleep induction has been a matter of some debate. Experiments using knockout mice suggest that it may be sufficient to antagonize only OX2R. The recent identification of an orally bioavailable, brain penetrant OX2R selective antagonist 2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (IPSU) has allowed us to directly test whether selective antagonism of OX2R may also be a viable strategy for induction of sleep. We have previously demonstrated that IPSU and suvorexant increase sleep when dosed during the mouse active phase (lights off); IPSU achieving this primarily by increasing NREM sleep, suvorexant primarily by increasing REM sleep. Here, we tested the effects of suvorexant and IPSU during the inactive phase (lights on), in order to determine their effects on sleep architecture during a phase when sleep is naturally more prevalent. At the doses tested, only suvorexant further decreased wake during the inactive period and only during the first hour after drug application. Whereas IPSU was devoid of effects on the time spent in NREM or REM, suvorexant substantially disturbed the sleep architecture by selectively increasing REM during the first 4 hours after dosing. Thus, OX2R selective antagonists may have a reduced tendency for perturbing NREM/REM architecture in comparison with DORAs. Whether this effect will prove to be a general feature of SORAs versus DORAs remains to be seen

Discovery of Umibecestat (CNP520): A Potent, Selective and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer’s Disease

Starting from lead compound 6, 5-amino-1,4-oxazine BACE1 inhibitors were optimised in order to improve potency, brain penetration and metabolic stability. Insertion of a Me and a CF3 group at the 6-position of the 5-amino-1,4-oxazine, led to 8 (NB-360) an inhibitor with a pKa of 7.1, a very low P-gp efflux ratio and excellent pharmacological profile enabling high CNS penetration and exposure. Fur color changes observed with NB-360 in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimen without any side effects and thus qualified for AD prevention studies in the clinic

Identification of a Novel Series of Orexin Receptor Antagonists with a Distinct Effect on Sleep Architecture for the Treatment of Insomnia

Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, SB-649868 or suvorexant, have shown promise for the treatment of insomnias and sleep disorders in several recent clinical trials in volunteers and primary insomnia patients. The relative contribution of antagonism of both OX1R and OX2R for sleep induction is still a matter of debate. We therefore initiated a drug discovery project with the aim of creating both OX2R selective and DORAs. Here we report that the OX2R selective antagonist 26 induced sleep in mice primarily by increasing NREM sleep, whereas the DORA suvorexant induced sleep largely by increasing REM sleep. Thus, OX2R selective antagonists may also be beneficial for the treatment of insomnia

Discovery of 1H-pyrazolo[3,4-b]pyridines as potent dual orexin receptor antagonists (DORAs)

Compound rac-1 was identified by high throughput screening. Here we report SAR studies and MedChem optimization towards the highly potent dual orexin receptor antagonists (S)-2 and (S)-3. Furthermore, strategies to overcome the suboptimal physicochemical properties are highlighted and the pharmacokinetic profiles of representative compounds is presented

Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360

Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic treatment regimens

Muscle Atrophy: Counteracting Muscle Atrophy on Earth and in Space via Nanofluidics Delivery of Formoterol

Skeletal muscle atrophy is a critical health problem that affects quality of life and increases morbidity and mortality. At present, exercise training remains the only intervention and pharmaceutical treatments remain elusive. Formoterol (FMT), a β2‐adrenergic receptor agonist, has emerged as a potential therapeutic by triggering skeletal muscle anabolism with daily dosing. Here, the efficacy of sustained FMT release is investigated via a subcutaneously implanted nanofluidic delivery system (nF) to prevent muscle wasting. Pharmacokinetics of nF‐mediated sustained FMT delivery (nF‐FMT) in healthy mice is assessed for 56 days, which demonstrates an anabolic effect on skeletal muscles. Using a hind limb suspension unloading mouse model, it is shown that nF‐FMT treatment attenuates soleus mass loss in comparison to control mice. Further, the very first study of an implantable drug delivery device in microgravity in vivo is launched. The microgravity environment aboard the International Space Station is leveraged to assess the atrophy prevention capability of nF‐FMT in mice for 29 and 55 days. Muscle hypertrophy is observed in both ground control and spaceflight mice treated with nF‐FMT compared to their respective vehicle controls. Overall, the nF system is presented as a viable platform for sustained delivery of FMT for therapeutic intervention of skeletal muscle atrophy