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.

Nuvalent’s lead compound, NVL-520, is an oral, brain-penetrant, TRK-sparing, and potential best-in-class ROS1 kinase inhibitor that recently entered Ph. II of the ARROS-1 trial (NCT05118789) in patients with advanced ROS1-positive NSCLC. This article highlights what makes the Nuvalent’s NVL-520 program scientifically notable, including what gives it a potential best-in-class profile as a ROS1 inhibitor, the emerging toxicology of hard-to-avoid off-targets, an interesting synthetic route to the small macrocycle, and more.

Recently, brain-penetration data via PET was reported for several KRAS(G12C) inhibitors including AZD4747, adagrasib, and sotorasib. AZD4747 has been updated with additional PET data for KRAS(G12C) inhibitors from a recent conference in the UK. Additionally, Tobias Biberger has contributed an update to the recent AZD4747 case study highlighting its interesting medicinal chemistry route with some surprising steps including manipulations of an unprotected phenol, and the synthesis of its PET tracer...

STX-478 is a wild-type-sparing, oral, CNS-penetrant, novel allosteric inhibitor of mutant phosphatidylinositol-3 kinase α (PI3Kα), targeting a cryptic pocket near the ATP-binding site. PI3Kα plays a central role in many cancers, and has been recently highlighted in coverage of 2021 Molecule of the Year nominee and PI3Kα degrader inavolisib. Currently approved PI3Kα modulators are limited by their off-target activities on WT PI3Kα and other kinases, leading to significant side effects including hyperglycemia and rash.

Nurix recently unveiled their second clinical BTK degrader, NX-5948, which is in Ph. Ia/Ib for patients with advanced B-cell malignancies (NCT05131022). A novel CRBN ligand was developed to remove IKZF1/3 degradation activity, distinguishing NX-5948 from their earlier disclosed dual BTK-IKZF1/3 degrader NX-2127, which is currently in Ph. I for relapsed/refractory B-cell malignancies (NCT04830137). The potent BTK degrader NX-5948 has displayed CNS penetration preclinically, allowing for primary CNS lymphoma (PCNSL) participants to be included in the clinical study.

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 [...]

Vorasidenib (AG-881) is a brain-penetrant allosteric inhibitor of mutant isocitrate dehydrogenases 1 and 2 (mIDH1/2) from Agios and Celgene that made headlines summer 2023 due to its stunning efficacy for treatment of glioma in patients with mIDH1/2.

This Featured Case Study reviews how it was discovered, how it works, and why it matters.

Recently, Novartis disclosed a new class of brain-penetrant, covalent agents against kinetoplastid parasites in Science. Kinetoplastid parasites cause Chagas disease (T. cruzi), sleeping sickness (T. brucei), and leishmaniasis (Leishmania), but there are few effective treatment options, especially for infections in the brain (e.g. stage II sleeping sickness).

AZD4747 is a CNS-penetrant, oral KRAS G12C covalent inhibitor for the treatment of CNS-metastatic KRAS-mutant cancers. KRAS inhibitors have tended to be quite large and fall outside the range of physicochemical properties generally required for CNS permeability. (MW < 360 Da, cLogD < 2, TPSA < 90 Å2. AZD4747 is much smaller than marketed KRAS G12C inhibitors but maintains exceptional cellular potency. The team also encountered an unexpected toxicity that scientists working on covalents should pay attention to.

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.

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.

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 [...]

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 [...]

In 2022, Turning Point Therapeutics ($TPTX) was acquired by BMS for a whopping $4.1 billion in cash. In November 2023, the most advanced molecule from Turning Point, repotrectinib, was approved for the treatment of ROS1+ NSCLC. This article explores the science behind repotrectinib, what made Turning Point so valuable, how we know, and what's next. [...]

Context. AZD1390 (recently published on by University of Minnesota) is a brain-penetrating Ataxia-Telangiectasia Mutated (ATM) kinase inhibitor under development for brain tumors. The kinase, known for its critical role in the repair of lethal DNA lesions induced by radiotherapy treatment, is considered an attractive target for CNS tumors [...]

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 [...]

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 [...]

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 [...]

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 [...]

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 [...]

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 Roche BRAF inhibitor, compound Ia, is designed to address the limitations of existing BRAFi/MEKi inhibitor combinations. It is a RAF paradox breaker (see belvarafenib) and is brain penetrant, offering the potential to address several mechanisms of resistance to approved agents and potentially reducing the need for MEKi combination [...]

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 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 Turning Point Therapeutics oral, brain-penetrant ALK/ROS1/TRK kinase inhibitor, repotrectinib (TPX-0005), is a macrocyclic molecule with a small size intended to limit adverse interactions with resistance mutation hotspots near kinase active sites. TRK fusion proteins are driver mutations in certain cancers (which respond well to [...]

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 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 cholesterol 24-hydroxylase inhibitor, soticlestat (TAK-935, previously OV935) is a potent, highly selective, first-in-class inhibitor of the brain-specific enzyme cholesterol 24-hydroxylase (CH24H). Cholesterol 24-hydroxylase converts cholesterol to 24S-hydroxycholesterol, which acts as a positive allosteric modulator of [...]

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)

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 [...]

“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 [...]

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.

CPI-1612 is a pretty efficient-looking EP300/CBP histone acetyltransferase (HAT) inhibitor tool compound with demonstrated activity in a xenograft model and good higher species PK. While epigenetics targets like HATs have been hot this decade, many programs have run into tolerability challenges and/or difficulty identifying activity [...]

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