One of the key challenges in CNS projects is achieving sufficient unbound brain exposure to engage the target. To predict CNS exposure, scientists employ metrics like CNS MPO scores from Pfizer and Merck, Bayesian models, and methods for balancing physicochemical properties. However, these in silico metrics often fail to correlate well with experimental data. Schrödinger's team has discovered the energy of solvation (E-sol) metric, which accurately predicts Kp,uu and has been validated with CNS-penetrant DLK inhibitors. Explore more in this detailed Drug Hunter article.

Cerevance’s CVN293 is an oral, CNS-penetrant, selective inhibitor of potassium efflux-mediated NLRP3-inflammasome activation in microglia for the treatment of neurodegenerative disorders. Cerevance’s NETSseq platform was used to discover a microglia-specific potassium efflux channel, KCNK13, which allows modulation of the NLRP3-inflammasome in the CNS without affecting peripheral innate immunity. Read the full article to discover highlights on the CNS-penetration of highly polar compounds and how particle size can be key to oral bioavailability

Zuranolone (ZURZUVAE™) is an oral positive allosteric modulator of CNS GABA signaling developed by Sage Therapeutics, in collaboration with Biogen, which was approved in August 2023 by the FDA for the treatment of postpartum depression (PPD). In 2019 Sage had received approval for brexanolone (ZULRESSO™), an IV formulation of the endogenous GABA PAM neurosteroid hormone for PPD, but an oral drug is expected to greatly increase access to treatment. Zuranolone was also investigated for major depressive disorder, although the FDA declined to extend approval for this indication.

If you are as excited as we are about this new era of non-opioid pain management and want to learn more, explore our series of articles that unravel the fascinating history of target validation of voltage-gated sodium channels, showcase the breakthroughs achieved so far, and look forward to what lies ahead for the industry.

The discovery that individuals with null mutations in the NaV1.7 exhibited pain insensitivity sparked interest in targeting NaV1.7 to potentially treat pain. Despite the potential of selectively inhibiting sodium channels like NaV1.7, NaV1.8, and NaV1.9 for pain management, developing selective inhibitors suitable for clinical use has proven challenging. This article complements our coverage of VX-548, NaV1.8 as a critical target in pain management, and our NaV1.8 compound roundup and provides a reminder of noteworthy preclinical and clinical NaV1.7 small molecule inhibitors as of April 2024.

NaV1.8, a member of the voltage-gated sodium channel (NaV) family, is predominantly expressed in peripheral sensory neurons. Based on rodent NaV1.8 knockout and knockdown studies and a 2012 report of gain-of-function mutations in humans, NaV1.8 has been linked to nociceptive, inflammatory, and neuropathic pain, including chronic neuropathic pain. This compound roundup provides a historical recap of both preclinical and clinical NaV1.8 inhibitors that shaped the landscape for the new era of pain management we are witnessing today.

NaV1.8 has become an industry focal point in the pursuit of pain therapeutics thanks to the success of Vertex’s selective inhibitor, VX-548, in Ph. III clinical trials for acute pain and Ph. II results in diabetic peripheral neuropathy. Unlike opioid receptor modulation, NaV1.8 inhibition does not carry the same addiction risks in part due to its lack of expression in the brain. Following our recent review of the leading NaV1.8 inhibitor VX-548, this article provides more details on the history of target validation for NaV1.8 in pain and why this could be the new frontier for pain management.

Vertex’s VX-548 is a potential first-in-class, exquisitely selective, oral NaV1.8 inhibitor that recently captured headlines for its positive Ph. III data. With the ongoing opioid epidemic throughout the US, there is an urgent unmet medical need for non-addictive pain medications as alternatives to opioids. They plan to file an NDA by mid-2024 for the treatment of moderate-to-severe acute pain. This case study highlights what’s publicly known about Vertex’s journey in pain leading up to the Ph. III readout for VX-548, and why this is such a watershed moment for pain management.

NT-0796 is NodThera's pro-drug inhibitor of the NLRP3 inflammasome. NT-0796 is currently in a Ph. Ib/IIa trial in obese individuals at risk of developing atherosclerotic cardiovascular diseases. NT-0796 has the potential to reduce neuroinflammation in Parkinson’s disease. The NLRP3 inflammasome has emerged as a hot target due to its connection to Alzheimer’s disease, Parkinson’s disease, gout, and other diseases. Here is a detailed review of the role of NLRP3 inhibition in treating atherosclerosis, how NT-0796 was identified and what makes it special, clinical development, and more.

JNJ-54175446 is an oral, CNS-penetrant P2X7 ion channel antagonist targeting a novel pathway linking neuroinflammation and depression, with recently published Ph. I data in major depressive disorder (NCT02902601, initiated in 2016). The Janssen program is notable as a pioneering early example of a neuroinflammation program started at a time before NLRP3 or neuroimmunology were commonly discussed topics, as they are today [...]

While SNRIs and selective serotonin reuptake inhibitors (SSRIs) have been hugely successful in treating major depressive disorder (MDD), many patients remain resistant to treatment or do not experience full symptom relief. The majority of current treatments for MDD increase levels of synaptic serotonin and/or norepinephrine by inhibiting their reuptake transporters SERT and NET, respectively.

LRRK2 has been a hotly pursued drug target for Parkinson’s Disease based on human genetics. Clinical advancement of LRRK2 inhibitors was initially stalled by concerns about on-target lung findings in primates, but these were ameliorated by a Merck/Genentech/Pfizer/MJFF study showing that these lung changes were reversible, and Biogen/Denali has currently a small molecule (BIIB122/DNL151) in Ph. II (NCT05348785) after demonstrating safety and CNS exposure in 145 healthy patients in Ph. I (NCT04557800)

TAK-994 is an oral, selective OX2R agonist developed by Takeda for the treatment of narcolepsy type 1 (with cataplexy) and type 2 (without cataplexy). The molecule follows Takeda’s previous clinical molecule, TAK-925 (danavorexton), which was the first OX2R agonist to be tested in people with NT1 but had poor oral bioavailability and was administered intravenously in the clinic.

Genentech announced that fenebrutinib (GDC-0853), a non-covalent BTK inhibitor entering Ph. III, showed significant human CNS exposure and reduced new brain lesions in Ph. II for relapsing multiple sclerosis. Fenebrutinib is the only reversible BTK inhibitor in Ph. III for MS, and has the opportunity to differentiate on safety relative to covalent inhibitors. This case study highlights notable challenges overcome in the discovery of fenebrutinib including surprising metabolism, animal-specific on-target toxicity, and more.

Camlipixant is an orally administered antagonist of the ATP-sensing P2X3 homotrimeric receptor ion channel, originated by AstraZeneca AB and assigned to the Canadian NEOMED Institute (now adMare), and developed by BELLUS Health (Canada), for the treatment of chronic cough. Chronic cough remains difficult to treat – the last FDA-approved anti-tussive, dextromethorphan, was first approved in 1958 and has demonstrated limited clinical efficacy.

DS-1971a is a potent, isoform-selective selective arylsulfonamide NaV1.7 inhibitor intended for the treatment of neuropathic pain. It has a surprisingly long residence time on NaV1.7, which the authors suggest contributes to better than predicted in vivo activity. 1971a is a good example of a compound which was successfully advanced to [...]

Kyowa Kirin’s KW-6356, or sipagladenant , is a non-xanthine A 2A receptor intended to treat Parkinson’s disease. Unlike Kyowa Kirin’s recently US-approved neutral antagonist, istradefylline, the molecule is an [...]

Pfizer has announced the FDA-approval of zavegepant ( ZAVZPRET TM , BHV-3500) for the treatment of acute migraine in adults based on positive Ph. II/III results. As the first and only calcitonin gene-related peptide (CGRP) receptor antagonist nasal spray [...]

Drug Hunter Reviewer Commentary. With over two decades of experience in neuroscience drug discovery, Drug Hunter reviewer Jake Schwarz says "mGluR2/3 agonists have been explored for schizophrenia, and agonists/PAMS could be tuned to give antagonist/NAM activity, but depression is a new indication. One of the more interesting depression [...]

Emraclidine (CVL-231) is a selective positive allosteric modulator (PAM) of the cholinergic M4 muscarinic receptor and is the only selective M4 PAM in clinical development. The molecule has shown promising early results in schizophrenia with several Ph. II trials enrolling and is intended to be developed for Alzheimer’s Disease psychosis as [...]

What is it? MK-8189 is a Ph. II clinical candidate for schizophrenia targeting PDE10A, a long-pursued but uncracked target for psychosis. With potentially better target engagement over prior molecules, it could become the first in the class to demonstrate efficacy in this challenging therapeutic area. The discovery and medicinal chemistry [...]

Emraclidine (CVL-231) is a selective positive allosteric modulator (PAM) of the cholinergic M4 muscarinic receptor (GCPR) and is the only selective M4 PAM in clinical development . The molecule was highlighted by Cerevel at JPM ‘23 as it has shown promising early results in schizophrenia with several Ph. II trials enrolling ( [...]

“Compound 25” is a selective, CNS-penetrant, ATP-competitive LRRK2 inhibitor that entered preclinical candidate enabling studies but was discontinued for undisclosed reasons. The molecule possesses two interesting chemical features: a “bow-tie” spirocyclopropyl group that made a significant impact on potency and overall properties [...]

DN-1289 is a CNS-penetrant, ATP-competitive DLK/LZK-selective dual kinase inhibitor intended to treat amyotrophic lateral sclerosis (ALS). The molecule is structurally closely related to Genentech’s recent Ph. I candidate, GDC-0134. Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are... [...]

An oral, brain-penetrant splicing modulator targeting ELP1. Incorrect splicing of the Elongator complex protein 1 (ELP1) gene causes Familial Dysautonomia (FD), a neurodegenerative disease that results in uncoordinated movement, blindness through retinal degeneration, and risk of unexplained sudden death, among other symptoms. A single T-to-C [...]

An old molecule and an old target come together. Squalamine was originally discovered in 1993 as an antimicrobial from the liver of the dogfish shark. It’s had a long and interesting history, investigated by Magainin/Genaera as a Ph. II antiangiogenic drug candidate for cancer and as a Ph. III opthalmic candidate for macular degeneration. One [...]

Context. BAY-069 (Bayer) is a branched-chain amino acid transaminase (BCAT) 1/2 inhibitor. Involved in the synthesis and breakdown of branched-chain amino acids, BCAT1 and BCAT2 have also been implicated in several diseases, including various cancer types, with the ligandability evidenced by the many reported inhibitors . Tool compound [...]

At AAPS 2022, I hosted a symposium where Ovoca Bio plc's Head of Research, Mikhail Lomonosov told us about orenetide. Orenetide is an internationally approved peptide drug for hypoactive sexual desire disorder (HSDD) (think Viagra for women). It appears to work within a few weeks in humans with a solid safety profile - Mikhail noted that one [...]

Context. Neflamapimod (EIP Pharma, VX-745 ) is an oral, brain-penetrant p38α kinase inhibitor under development for neurodegenerative disorders. Among the roles of p38α MAPK is the activation of Rab5 , a small endosome-associated Ras GTPase that regulates intracellular trafficking pathways . This, coupled with the involvement of Rab5 in the [...]

Spinal Muscular Atrophy (SMA)—the leading genetic cause of childhood mortality—is a disease in which the gene SMN1 is deleted or mutated. The highly similar gene SMN2 can undergo alternative splicing to generate functional protein transcripts of the SMN1 gene product, although native levels of the protein are too low to overcome the pathology [...]

Context. SAGE-718 (Sage Therapeutics) is an oral N -methyl-d-aspartate receptor (NMDAR) Positive Allosteric Modulator (PAM) being developed for cognitive impairment in Huntington’s disease. Aberrant NMDAR signaling has been implicated in several neurological and psychiatric disorders, making the receptor an attractive drug target. Although [...]

This article is Part 5 of a review series covering all the initial public offerings for the biotech and pharmaceutical industries in 2021. Part 1 and Part 2 provided an overview of 2021 IPOs by therapy area, technology, and therapeutic class. Part 3 and Part 4 provided a deep dive into the 2021 IPOs for oncology-focused companies developing [...]

Context. Iclepertin (BI 425809; Boehringer Ingelheim) is an oral glycine transporter-1 (GlyT1) inhibitor being developed for cognitive impairment associated with schizophrenia (CIAS) . The ineffectiveness of currently available antipsychotic medications in improving negative symptoms and cognitive deficits leaves a significant unmet need for [...]

Context. DNL201 (Denali Therapeutics) is an oral, CNS-penetrating, ATP-competitive leucine-rich repeat kinase 2 (LRRK2) inhibitor being developed for Parkinson’s disease (PD) . PD remains incurable; current treatment options only alleviate disease symptoms and do not prevent progression. Due to its well known involvement in familial and even [...]

A first-in-class intravenous kappa opioid receptor (KOR) agonist, an oral soluble guanylate cyclase (sGC) stimulator, a first-in-class subcutaneous complement C3 inhibitor, and an oral contraceptive comprising a synthetic progesterone (drospirenone) and a plant-based estrogen (estetrol) make up the final group of novel drugs from 2021 that we [...]

Context. “Compound 20” (Gedeon Richter) is an oral α5-GABA A receptor negative allosteric modulator (NAM) being developed for cognitive disorders . GABA receptor NAMs are known to exert effects opposite to the anxiolytic and anticonvulsant effects of positive allosteric modulators. However, NAM agents targeting α5-GABA A receptors, which have [...]

Context. ABBV-318 (AbbVie) is a CNS-penetrating, oral inhibitor of Na v 1.7/Na v 1.8 being developed for pain treatment . Despite being a highly validated pain target due to its important role in excitable cells, Na v 1.7 inhibition has not lived up to its potential, and translation of the promising preclinical observations to human studies [...]

Context. Lenrispodun (Intra-Cellular Therapies) is a phosphodiesterase (PDE) type 1 (PDE1) inhibitor being developed for CNS and non-CNS disorders, including heart failure, and cancer. Studies to identify PDE inhibitors date back at least 30 years, and at least 10 drugs have been approved targeting other PDE proteins (spearheaded by the PDE5 [...]

Context. BMS-986176/LX-9211 (BMS) is an oral, CNS-penetrable AAK1 kinase inhibitor being developed for treatment of neuropathic pain . There are six main classes of pain medications, NSAIDs, opioids, ion channel modulators, serotonergic, monoaminergic, and GABAnergic drugs that are broadly used for pain in general, but neuropathic pain due to [...]

Context. Branaplam (Novartis Institutes for Biomedical Research) is an oral brain-penetrant splicing modulator, originally developed as a small molecule splicing modulator for spinal muscular atrophy (SMA). It turns out to also lower huntingtin levels and is being developed (with Fast Track Designation ) for patients with Huntington’s Disease [...]

Context. HR1405-01 (Nanjing Heron Pharmaceutical) is an intravenous NSAID with inflammatory and analgesic activities. Oral NSAIDs (ibuprofen, naproxen..) are widely used, and it is interesting to see justification for a new intravenous NSAID. Intravenous ibuprofen was the first intravenous NSAID to be approved, following which a couple of [...]

This article reviews the three novel drugs approved by the FDA in March 2022 in detail. together with Dr. Naveed Yasin, Jesse Keicher, Dr. Jennifer Huen, and Dr. Adrian Parodi Small molecules: Ztalmy ® ( ganaxolone ): An oral GABAA receptor positive allosteric modulator to treat seizures in cyclin-dependent kinase-like 5 deficiency disorder [...]

The FDA approved five novel small molecule drugs in neurology in 2021. Addressing a range of conditions from ADHD to relapsing MS, the 2021 neurology drug approvals are: atogepant (Qulipta): calcitonin gene-related peptide (CGRP) receptor antagonist ponsimod (Ponvory): selective sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) modulator [...]

Context. LY3154885 (Eli Lilly and Company) is an oral D1 modulator. Lilly recently completed several clinical trials with LY3154207 ( mevidalen ), the first D1 positive allosteric modulator (D1PAM) with published clinical data, in Parkinson’s disease ( NCT02562768 ), sleep ( NCT02603861 ), and lewy body dementia (LBD) ( NCT03305809 ). In [...]

Context. Danavorexton (Takeda, TAK-925) is a CNS-penetrant, injectable OX2 agonist. Orexin receptor (OX1/OX2) antagonists (e.g. daridorexant ) are approved for treatment of insomnia. Orexin agonism would be expected to have the opposite effect, promoting wakefulness rather than sleep, which is helpful for patients with narcolepsy (difficulty [...]

Context. T-690 (Takeda) is an oral GCS inhibitor that is brain-penetrant, non-basic, and non-competitive with UDP-glucose. We recently highlighted a glucosylceramide synthase (GCS, aka CGT) inhibitor in Ph. III (Sanofi’s venglustat ). GCS inhibition may reduce glycosphingolipid levels downstream of its product, glucosylceramide (GlcCer). GCS [...]

compound 1 is a CD33 pre-mRNA splicing modulator that increases CD33 exon 2 skipping in cells. CD33/Siglec 3 regulates microglia activity, and genetic alterations of CD33 are associated with protection from Alzheimer’s. Alternative splicing of CD33 with exclusion of exon 2 is hypothesized to copy the protective effect of the human genetic [...]

There were four novel drugs approved by the FDA in January 2022 (2 small molecules, 2 large molecules). The novel January 2022 new drug approvals appear below in this Drug Hunter minireview: See our overview of all 36 of the novel small molecule and large molecule FDA [...]

Mutated Huntingtin (HTT) protein is the cause of Huntington’s disease (HD). HTT-D3 is an oral, CNS-penetrant molecule with human HTT lowering activity in vivo used to illustrate the science around PTC Therapeutics’ Huntingtin’s disease program. PTC had filed patent applications for the HD program as early as November 2016 ( WO201700726 ). PTC [...]

Ulotaront (SEP-363856) is a Phase III candidate with FDA Breakthrough Therapy Designation for the treatment of schizophrenia with demonstrated efficacy based on a physician-rated scale (PANSS) in a 4-week placebo-controlled trial and continued improvement in an open-label extension study. Reviewer Jake Schwarz says, “ulotaront was developed [...]

Vertex recently disclosed a CNS-penetrant ELOVL1 inhibitor, in which they described preclinical safety findings in rat and cyno. In this article, they disclose a structurally distinct series which displayed similar ocular toxicity in rat, and skin and CNS toxicities in cyno. A third structurally distinct series (undisclosed) also showed [...]

LRRK2 is a target of interest for Parkinson’s disease (e.g. DNL-151 ), but development had been slowed by concerns about potential lung toxicity of LRRK2 inhibitors. A Phase I study of a LRRK2 inhibitor in healthy volunteers had not shown human toxicity, though, and Biogen/Denali plan to proceed with Ph. III and Ph. IIb trials in 2022 . The [...]

The Biogen reversible BTK kinase inhibitor, BIIB091, is a highly selective, phase I clinical candidate for multiple sclerosis. Irreversible BTK inhibitors have been explored and developed extensively, primarily in cancer. Reversible molecules have been less common, with the most clinically advanced molecule being fenebrutinib (phase [...]

The Vertex ELOVL1 inhibitor, compound 27, is a potent (13 nM) CNS-penetrant compound that reduces very long chain fatty acid (VLCFA) levels in the CNS, which are believed to be pathological in the rare disease adrenoleukodystrophy (ALD). The starting point came from an HTS on compounds from an internal collection. The molecule demonstrated [...]

The Takeda GPR139 agonist, TAK-041 , is a CNS-penetrant GPCR agonist being explored for schizophrenia symptoms and is an interesting example of a triazinone-containing clinical candidate. GPR139 is an orphan GPCR that’s highly expressed in the human habenula, which plays a major role in avoidance behavior. Lesions in the habenula cause [...]

The Takeda AMPA-R potentiator, TAK-653 , is a glutamate-dependent potentiator that exhibits minimal agonism. AMPA-R agonism is associated with seizure risk and bell-shaped dose-response effects. As reviewer Jake Schwarz notes, companies including Cortex Pharmaceuticals (now RespireRx) and Lilly have been trying to develop AMPA modulators for [...]

The Altos Therapeutics /Takeda D2/D3 receptor antagonist, TAK-906 , is a peripherally-restricted, non-BBB penetrant molecule, targeting the stomach and vomiting center in the area postrema to treat gastroparesis. Gastroparesis is a chronic condition characterized by delayed gastric emptying, resulting in nausea, vomiting, pain, and anorexia [...]

The Takeda brain-penetrant M1R positive allosteric modulator (PAM), TAK-071, was optimized for lower cooperativity (α) with the native ligand to theoretically reduce the side effect of diarrhea from M1R activation. In animal models, higher cooperativity on M1R was associated with diarrhea, while lower cooperativity led to a wider margin. In [...]

The BMS AAK1 kinase inhibitor, compound 59 , is brain-penetrant and acts on the CNS. The target was identified from a phenotypic screen of mouse knockouts, and a non-brain penetrant inhibitor doesn’t show in vivo activity, confirming the central activity needed on the target. Targeting a kinase in the CNS for pain is bold due to the high bar [...]

The Bayer P2X3 purinoreceptor antagonist, eliapixant (BAY1817080), is intended to treat various disorders associated with hypersensitive nerve fibers, including endometriosis. The hypothesis is that P2X3 receptor antagonism can inhibit cycles of pain causing neurogenic inflammation, causing pain, etc. modifying the underlying disease in [...]

The Sanofi glucosylceramide synthase (GCS) inhibitor, venglustat , is an oral, brain-penetrant clinical candidate for GBA -mutant Parkinson’s disease and other diseases where GBA -mutations are relevant. Though the molecule did not demonstrate efficacy within one year in early GBA -PD patients and was discontinued in this indication [...]

The FORUM Pharmaceuticals CNS-penetrant gamma secretase inhibitor and preclinical candidate, FRM-024 , is an advanced example of the use of an oxadiazine as an amide isostere . While amide isosteres are frequently proposed, it is often difficult to implement them beyond basic heterocyclic replacements. A benzofuran structural alert was [...]

The Janssen BACE1-selective inhibitor, JNJ-67569762 , was a preclinical candidate for Alzheimer’s disease. Obtaining BACE1 over BACE2 selectivity was a major challenge in the field, and the molecule is 74x selective thanks to a bicyclic ring system in the S3 pocket. In in vivo models, BACE1-mediated PD was observed without BACE2-dependent [...]

The EicOsis oral soluble epoxide hydrolase (sEH) inhibitor, EC5026, is a compound currently intended as a non-opioid analgesic and anti-inflammatory agent. It recently completed a Ph. I study in healthy volunteers without drug-related adverse events. Despite its small size, it has picomolar binding activity with the urea acting as an [...]

The Shionogi BACE1 aspartyl protease inhibitor, atabecestat (JNJ-54861911) is an oral, brain-penetrant compound that was advanced into the EARLY Ph. IIb/III clinical trial for treatment of preclinical Alzheimer’s disease (AD) patients. The starting point was identified from a phenotypic HTS, and was the first thiazine-based BACE1 disclosed [...]

The Xenon NaV1.6 Inhibitor, NBI-921352 , is remarkably selective for the NaV1.6 sodium channel over other isoforms (IC50 = 51 nM, 756x vs. NaV1.1, 134X vs. NaV1.2, 276X vs. NaV1.7, >583X vs. 1.3, 1.4, 1.5). The molecule is It is being developed to treat pediatric patients with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) and [...]

The Takeda MAGL inhibitor, “compound 4f” , was selected by reviewer Joachim Rudolph . “MAGL (monoacylglycerol lipase) is implicated in neuroinflammation, and inhibitors of this enzyme are of interest as therapeutics in neurodegenerative and other neurological diseases. Most of the advanced compounds, including the clinically evaluated [...]

The Cerevance/Takeda GPR6 inverse agonist (CVN424) is an oral, once-daily clinical candidate in Ph. II for Parkinson’s disease after completing a Ph. I in healthy volunteers. Its >40 µM starting point was discovered through a 360k compound cell-based HTS targeting human GPR6 (an orphan GPCR). The molecule CVN424 is interesting because it is [...]

“EST73502” (ESTEVE oral dual mu-opioid receptor agonist, sigma-1 receptor antagonist clinical candidate)

“compound 46” (Janssen oral selective brain-penetrant PDE2A phosphodiesterase inhibitor)

“compound 3d” is a prodrug which is phosphorylated in vivo to form a potent sphingosine-1-phopshate receptor modulator. BMS took two previous compounds into the clinic for MS with the goal of differentiating from fingolimod on safety. One potential issue for a previous compound was an overly long (12 day) half-life which could be undesirable [...]

Vixotrigine (BIIB074) is a voltage-gated sodium channel blocker that preferentially binds to the inactivated state of the sodium channels, conferring selectivity for channels involved in pain-associated high frequency nerve signalling over normal low frequency nerve signalling (use-/state-dependence). The use-dependent activity is believed to [...]

DS34942424 is a potent oral analgesic discovered using the natural product conolidine as a starting point. While the authors were able to demonstrate that the compound does not exert its activity through the mu-opioid receptor, the mechanism of action is not understood. The identification of non-opioid analgesics are an area of intense [...]

“compound 12” is a selective negative allosteric modulator of the GluN2B subunit of NDMA receptors intended for treatment of mood disorders. In this program, poor solubility and permeability were a challenge for oral exposure, but was addressed with a nanosuspension formulation. The nanosuspension allowed them to get high enough margins in [...]

“compound 20” is a gamma-secretase modulator (GSM) with an interesting, uncommon oxadiazine scaffold. Like many hot areas in drug discovery, the GSM area for Alzheimer’s has led to many creative chemical scaffolds. It’s always interesting to see how these new scaffolds behave. This compound demonstrates surprisingly low clearance, high [...]

HTL22562 is a CGRP antagonist intended to treat acute migraines. Some prior oral CGRP antagonists failed in clinical trials due to liver tox. signals, so this program targeted a non-oral candidate with lower first-pass liver exposure that might avoid such issues. Impressively the authors were able to drive the program through structure-based [...]

MGS0274 is a prodrug of an mGlu2/3 receptor agonist with ca. 15x greater oral exposure than the parent. The ester is believed to be cleaved pre-systemically by liver carboxyesterases to release the innocuous byproducts acetaldehyde, CO2, and menthol. The parent is also an interesting looking molecule prepared in a few steps from [...]

“Compound 19” is a selective brain-penetrant inhibitor of the ceramide galactosyltransferase UGT8, intended for use in substrate reduction therapy for rare lysosomal storage disorders. The compound has good oral exposure in higher species (%F = 52 in dog) and is active in models looking at enzymatic activity using isotopically-labeled [...]

[18F]LSN3316612 is a PET radiotracer for quantifying levels of O-GlcNAc hydrolase (OGA) in the brain. OGA is an enzyme involved in the post-translational modification of tau protein, and OGA may be a useful biomarker for neurodegenerative disease drug development. The fluorine radiolabel was introduced through nucleophilic aromatic [...]

RO7185876 is a gamma-secretase modulator (GSM) intended for treatment of Alzheimer’s disease. GSMs, which act by stabilizing the enzyme/substrate complex to promote generation of shorter peptides rather than inhibiting enzyme activity, and hence are anticipated to be less toxic than gamma-secretase inhibitors (GSI’s) which were abandoned due [...]

“Compound 15” is a BACE1 selective inhibitor with a fluoro-olefin replacement for an N-aryl amide without the liability of a potential aniline metabolite. The compound has good oral PK in rodents, which was likely challenging to obtain with the thioamidine core common to BACE1 inhibitors. As usual for Amgen there’s some pretty cool synthetic [...]

JNJ-54717793 is a selective antagonist of the orexin-1 receptor intended for use in anxiety disorders, in contrast to dual orexin-1/2 inhibitors and orexin-2 inhibitors typically applied for sleep disorders. It’s a surprisingly large molecule (three aromatic rings and a bicycle) for an oral, brain-penetrant clinical candidate with predicted [...]

DS-1971a is a potent, isoform-selective selective arylsulfonamide NaV1.7 inhibitor intended for the treatment of neuropathic pain. It has a surprisingly long residence time on NaV1.7, which the authors suggest contributes to better than predicted in vivo activity. 1971a is a good example of a compound which was successfully advanced to [...]

“Compound 6g” is a potent, selective, and reversible inhibitor of monoacylglycerol lipase (MAGL), which degrades the cannabinoid receptor (CB) agonist 2-arachidononylglycerol (2-AG) to arachadonic acid (AA). Inhibition of MAGL therefore indirectly agonizes CB receptors and reduces inflammatory AA levels, which may be beneficial for a range of [...]

LEI401 is a selective, brain-penetrant inhibitor of NAPE-PLD, an enzyme involved in the biosynthesis of various N-acylethanolamine (NAE) signaling lipids, and is a potentially useful tool molecule for understanding the basic biology around this target. The compound emerged as the result of an academic collaboration, including an HTS done with [...]

S6821 is one of two potent and selective TAS2R8 GPCR antagonists disclosed by Firmenich, a fragrance and flavor company. These compounds block bitter taste receptors and don’t have significant systemic exposure, and have been approved as safe for use. I thought it was interesting to see high-quality medicinal chemistry applied in a [...]

ORN0829 is a dual inhibitor of orexins 1 and 2, designed to have a relatively short half life in humans for application in insomnia (to reduce side effects after waking up). Chemically it has an interesting chiral 1,3-oxazinane amide motif, which is resolved in their med. chem. route through an enzymatic resolution.

“Compound 9” is the first potent M3-selective positive allosteric modulator, with potential utility as a biological tool compound. It does have secondary activity against M5 at high doses though. It’s quite a large zwitterion, which is somewhat unusual for GPCRs.

FT385 is a covalent inhibitor of the USP30 deubiquitinating enzyme with a cyanopyrrolidine warhead. Identifying selective active-site inhibitors of de-ubiquitinating enzymes has been challenging, and FT385 now provides a good tool compound to study USP30 biology. Some of my colleagues at Genentech recently published on the mechanism of [...]

MK-6884 (Merck M4 positive allosteric modulator PET tracer) 2022 Update: Human Ph. I data disclosed in https://doi.org/10.1126/scitranslmed.abg3684