“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 37” is an inhibitor of the ATG7 E1 ligase through an interesting substrate-assisted covalent mechanism. Rather than covalently modify ATG7 directly, the molecule reacts with the E1 ligase substrate, Ubl, to form a Ubl-inhibitor adduct which non-covalently inhibits ATG7. This mechanism has been employed by Takeda successfully in the [...]

“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 [...]

A-1331852 is a highly potent, orally bioavailable inhibitor of BCL-XL, blocking a protein-protein interaction resulting in tumor cell apoptosis. The compound was an important tool compound for understanding the biology of BCL-family protein inhibitors (particularly around heme toxicities), and ultimately led to the development of an [...]

dotinurad (FYU-981) potently inhibits uric acid uptake by renal proximal tubule epithelial cells, increasing uric acid urinary secretion which can help hyperuricemic conditions like gout. The mechanism of action is believed to be inhibition of the URAT1 organic anion transporter which mediates uric acid reabsorption. Benzbromarone has been [...]

X-165 is an autotaxin inhibitor clinical candidate for idiopathic pulmonary fibrosis discovered using a 3-cycle DEL screen of 225M compounds derived from amide couplings. An unusual spirocyclic amine building block was responsible for most of their non-phosphonate-containing high-enrichment hits. The initially resynthesized hits had [...]

“compound 38a” is an inhibitor of ChemR23, a chemokine-receptor-like GPCR with a role in plasmacytoid dendritic cell (pDC) trafficking. The ChemR23 inhibitor was developed with the intention of suppressing the migration of pDCs, which may be useful in certain autoimmune diseases. A key change that dramatically improved bioavailability was [...]

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 [...]

“compound 23” is an oral, selective Factor XIa inhibitor intended as an anticoagulation agent. Since the clinical translatability of FXIa inhibition in preclinical models hasn’t been established, this program was driven by activity in in vitro human plasma coagulation assays. The team was able to turn a 0.6 uM hit originally from a complement [...]

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 [...]

LXE408 is an oral antileishmanarial compound that selectively targets the kinetoplastid proteosome vs. the mammalian proteosome. The prior candidate, GNF6702, had solubility-limited oral absorption, which could have been addressed with a specialized formulation but would have increased the cost and limited use in developing countries. A [...]

“compound 2” is a heme-displacing IDO1 inhibitor with a similar binding mode to BMS-986205 with a low projected human dose. A bis-amide hit was generated from a mass-spectrometry based binding screen, and optimized through structure-based drug design. An initial benzamide lead was metabolically unstable due to rapid amide hydrolysis, but this [...]

AB680 is a potent (5 pM) and selective inhibitor of CD73, a nucleotidase that metabolizes AMP to immunosuppressive extracellular adenosine. AB680 is intended to be used in combination with checkpoint inhibitor biologics in cancer immunotherapy, and has a PK profile for biweekly (Q2W) IV dosing in humans based on a Ph. I study in healthy volunteers.

“compound 18” is an oral inducer of fetal hemoglobin (HbF) intended to treat anemias such as sickle cell disease and beta-thalassemia. The authors identified a weak hit (>10 uM) from a high-throughput phenotypic screen using human umbilical cord blood-derived erythroid progenitor cells. Optimization led to the azaspiro[3.3]heptane-containing [...]

ETX0282 is an oral prodrug of a class A, C, and D serine β-lactamase inhibitor in clinical development for drug-resistant enterobacterial infections in combination with the beta-lactam drug cefpodoxime proxetil. Impressively ETX0282 had no observed adverse effect levels (NOAELs) of 500 mg/kg/day and 400 mg/kg/day in rat and dog, respectively, [...]

“compound 6g” is an oral inhibitor of the sodium-glucose co-transporters (SGLTs) 1 and 2, intended for the treatment of hyperglycemia. SGLT2 selective inhibitors (gliflozins) are approved for treatment of type 2 diabetes, and an SGLT1/2 dual inhibitor is expected to result in greater glycemic control. Like other SGLT inhibitors, this molecule [...]

EC2629 is a folate receptor (FR)-targeted small molecule drug conjugate with a folate receptor-targeting moiety, a pyrrolobenzodiazepine (PBD) DNA-crosslinking warhead, and a linker. Similar to antibody-drug conjugates, this small molecule conjugate is intended to maintain the activity of the potent PBD warhead while minimizing systemic [...]

BAY 1003803 is a potent topical agonist of the glucocorticoid receptor (GR) transrepression pathway, with less activity on the GR transactivation pathway mediated by GR dimers, which may lead to undesirable side effects. The fluoroaminoquinoline was the only heterocycle among analogs tested that was Ames-negative. The compound appears to have [...]