Seven science items today: a G2019S-selective LRRK2 series, a siderophore–ampicillin conjugate, dual BuChE/FAAH inhibitors, an IL-11 antagonist peptide, LasB inhibitors from kinetic target-guided synthesis, masked ASM inhibitors and a binding-energy GNN. Business: Viatris–Pacira and a Life Biosciences glaucoma update.
2026-10-10 · ⚗️BuChE / FAAH (dual inhibitors) · Journal of Medicinal Chemistry (ACS)
- Donepezil-based derivatives were designed and made as dual inhibitors of human butyrylcholinesterase and fatty acid amide hydrolase.
- Lead G15 inhibited both enzymes in a balanced way, with sub-micromolar to low-micromolar activity.
- It showed measurable selectivity over the carboxylesterases CES1 and CES2, a common liability for serine-hydrolase inhibitors.
💡 PointsDual-target hybrids rarely land balanced potency on both enzymes, so G15 is a useful starting point. Selectivity over carboxylesterases is only modest, though, and I'd want in vivo exposure data before believing the multi-target rationale.
Design, Synthesis and Evaluation Donepezil-Based Dual BuChE/FAAH Inhibitors for Alzheimer's Disease Therapy ↗
2026-10-10 · ⚗️LRRK2 (G2019S mutant-selective inhibitors) · ACS Medicinal Chemistry Letters (ACS)
- Structure-guided hybridization of an indazole with an octahydrocyclopenta[c]pyrrole gave a new LRRK2 inhibitor chemotype for Parkinson's disease.
- Early piperidine-containing analogs were potent but barely distinguished wild-type from G2019S LRRK2.
- Swapping the piperidine for the fused bicyclic amine was the change introduced to widen that selectivity window.
💡 PointsA narrow wild-type/G2019S window is the usual reason LRRK2 leads stall, so a scaffold change that buys mutant bias is worth a look. I'd want to see whether that bias holds in cells at physiological ATP and what the bicyclic amine does to brain penetration and clearance.
Discovery of G2019S Mutant Selective LRRK2 Inhibitors Based on an Indazole Octahydrocyclopenta[c]pyrrole-Based Hybrid Chemotype ↗
2026-10-10 · ⚗️Siderophore–β-lactam conjugates (P. aeruginosa) · Journal of Medicinal Chemistry (ACS)
- A Trojan-horse design hijacks bacterial iron uptake to move a β-lactam payload across the Gram-negative outer membrane.
- Ampicillin was conjugated to mono-catecholate, bis-catecholate and catecholate–hydroxamate siderophores and the series compared.
- The bis-catecholate conjugate is reported as the selective one, extending ampicillin's reach to multidrug-resistant P. aeruginosa.
💡 PointsGetting an old penicillin to work on Pseudomonas by changing only the delivery vector is a clean demonstration of the siderophore approach. Linker stability in serum and the chance that resistant strains simply down-regulate the uptake receptors are the things I'd check next.
A Selective Bis-Catecholate Siderophore-Ampicillin Conjugate Expands Activity against Multidrug-Resistant Pseudomonas aeruginosa ↗
2026-10-08 · ⚗️IL-11 (cyclic peptide antagonist) · ACS Medicinal Chemistry Letters (ACS)
- The oxidation-sensitive thioether in an IL-11-binding peptide was replaced with a lactam bridge, with linker length screened systematically.
- The optimized analog 4L6–16 bound IL-11 with good affinity and antagonized it more strongly than the starting peptide.
- It showed renoprotective effects in both cell and animal models of renal fibrosis.
💡 PointsSwapping a thioether for a lactam is a textbook peptide-stability fix, and it's encouraging that it also improved antagonism rather than just shelf life. Binding in the mid-nanomolar range leaves room to tighten, and proteolytic stability in plasma is the next number I'd ask for.
Development of a Lactam-Bridged Peptide as Interleukin-11 Antagonist for Renal Fibrosis Treatment ↗
2026-10-08 · ⚗️LasB elastase (antivirulence, kinetic target-guided synthesis) · chemRxiv
- Guided by earlier crystal structures, kinetic target-guided synthesis was used to assemble inhibitors of the P. aeruginosa virulence factor elastase LasB.
- Extensive SAR gave hydroxamic acid inhibitors with very high potency and good selectivity over a panel of human off-targets.
- The compounds protected lung epithelial cells from LasB damage, showed in vivo efficacy, and reached lung exposure above their biochemical potency.
💡 PointsUsing the enzyme itself to pick its best fragment pairs is a smart way into a metalloprotease pocket, and the lung PK above IC50 is exactly the data antivirulence programs usually lack. Hydroxamates still carry metabolic and zinc-binding baggage, so the off-target panel on other metalloenzymes is where I'd look first.
Kinetic Target-Guided Discovery of Selective Nanomolar Hydroxamic Acid–Based Inhibitors of Pseudomonas aeruginosa Elastase LasB ↗
2026-10-08 · ⚗️Acid sphingomyelinase (prodrug-style masked bisphosphonates) · ACS Chemical Biology (ACS)
- The charged amino bisphosphonate inhibitor ARC39 of acid sphingomyelinase was masked to improve cell entry.
- Masked derivatives reached nanomolar activity in cells, about two orders of magnitude better than the parent.
- Cell uptake, stability and related properties were characterized in detail.
💡 PointsPhosphonate masking is a familiar trick, but ASM has lacked a potent cell-active tool, so a hundred-fold gain in cells matters for target validation. Whether the masks unveil cleanly in the lysosome, where ASM works, decides if this is a probe or a lead.
Masked Bisphosphonate Inhibitors of Acid Sphingomyelinase: Improved Cell Penetration and Potency ↗