CPP-115 / Catalyst Pharma, Angelini Group - LARVOL DELTA

Targeting conformational flexibility of a reactive intermediate to enhance selectivity of a GABA aminotransferase inactivator (ACS-Fall 2026) - "Our strategy in this study, targeting dynamics of a reactive intermediate based on a precise mechanistic understanding, serves as a general design principle for fine-tuning the selectivity of MBIs, particularly for other aminotransferases. Mechanism of hOAT inactivation by CPP-115 and enhanced selectivity by (S)-MeCPP-115 Design strategy and enzyme inactivation activity of (S)-MeCPP-115 (5)."

Breaking a translational barrier in the development of a GABA aminotransferase inactivator (ACS-Fall 2026) - "CPP-115 has demonstrated strong therapeutic potential as a next-generation inactivator of GABA aminotransferase (GABA-AT) with markedly improved potency and safety compared to the only clinically available GABA-AT inactivator, vigabatrin. Based on this insight, a next-generation inactivator with substantially improved selectivity was developed and is now undergoing preclinical evaluation as a potentially safer candidate. Future directions with this molecule include proteomic profiling to systematically validate the selectivity across homologous enzymes and the development of activity-based probes, offering potential avenues for both therapeutic advancement and translational applications."

CNS Disorders • Epilepsy

Targeting Conformational Flexibility of a Reactive Intermediate to Enhance Selectivity of a GABA Aminotransferase Inactivator. (PubMed, J Am Chem Soc) - "For example, CPP-115, an MBI of GABA-AT that completed a Phase I clinical trial, also inactivates ornithine aminotransferase (OAT)...The resulting inactivator achieved greatly enhanced GABA-AT selectivity over OAT and demonstrated therapeutic efficacy in an inflammatory pain animal model. Our strategy in this study, targeting dynamics of a reactive intermediate based on a precise mechanistic understanding, serves as a general design principle for fine-tuning the selectivity of MBIs, particularly for other aminotransferases."

Journal • Pain

A newly designed GABA-AT inactivator, ( S )-MeCPP-115, suppresses paclitaxel-induced neuropathic pain in mice. (PubMed, bioRxiv) - "Selective GABA-AT inhibition represents a promising therapeutic approach for suppressing paclitaxel-induced mechanical hypersensitivity. Further preclinical characterization of the therapeutic profile of ( S )-MeCPP-115 is warranted."

Journal • Preclinical • Breast Cancer • Immunology • Neuralgia • Oncology • Pain • Peripheral Neuropathic Pain • Solid Tumor

Novel GABA aminotransferase and ornithine aminotransferase inactivators and potential new treatments for epilepsy, neuropathic pain, and hepatocellular carcinoma (ACS-Fall 2024) - "Several analogues related to CPP-115 were identified that do not inactivate GABA-AT but are potent inactivators of OAT. Enzyme inactivator design and mechanism studies will be discussed, as well as in vitro and in vivo efficacy and pharmacokinetic results, toxicology studies, and a clinical trial with CPP-115."

CNS Disorders • Epilepsy • Gastrointestinal Cancer • Hepatocellular Cancer • Neuralgia • Oncology • Pain • Solid Tumor

Monosodium Urate and Calcium Pyrophosphate Crystal-induced Inflammation Relies on Cell Volume Regulation and LRRC8/VRAC Channel Activation (ACR Convergence 2023) - "Similarly, IL-1β production induced by MSU and CPP crystals was substantially decreased in WT THP-1 treated with DCPIB (MSU 5200 vs 1080 pg/ml; CPP 11500 vs 4980, p< 0.0001) and in shLRRC8A THP-1 cells compared to crystal-treated WT cells... These results suggested that MSU and CPP crystal-induced inflammation involves cell volume variation regulated by VRAC/LRRC8 channel. T. Wilson Chirayath:; m. kayatekin:;"

Immunology • Inflammation • Rheumatology • IL1B • LRRC8A • NLRP3

Monosodium urate and calcium pyrophosphate crystal-induced inflammation relies on cell volume regulation and LRRC8/VRAC channel activation (EULAR 2023) - "Similarly, IL-1β production induced by MSU and CPP crystals was substantially decreased in WT THP-1 treated with DCPIB (MSU 5200 vs 1080 pg/ml; CPP 11500 vs 4980, p<0.0001) and in shLRRC8A THP-1 cells compared to crystal-treated WT cells...In vivo, inflammation induced by MSU and CPP crystals assessed in lavage fluid and conventional histology was lower in Cxcr3Cre_Lrrc8aflox/flox mice as compared with wild-type mice in terms of IL-1β production and cell infiltrate. Conclusion These results suggested that MSU and CPP crystal-induced inflammation involved and cell volume variation regulated by VRAC/LRRC8 channel."

Inflammation • Rheumatology • IL1B • LRRC8A • NF-κβ • NLRP3

Identification of novel C-15 fluoro isosteviol derivatives for GABA-AT inhibition by in silico investigations. (PubMed, J Mol Model) - "The results revealed that all fluoro isosteviol analogs displayed a greater binding affinity than references vigabatrin, an FDA-approved GABA-AT inactivator, and CPP-115, which has Orphan Drug Designation status, and positioned at the same binding site as references. The Open Babel software was utilized for extracting SMILEs files of all the fluoro isosteviol analogs. The drug-likeness and ADMET of the molecules were evaluated by SwissADME and ADMETlab 2.0 web tools."

Journal • CNS Disorders • Epilepsy

Novel GABA aminotransferase and ornithine aminotransferase inactivators and potential new treatments for epilepsy, neuropathic pain, and hepatocellular carcinoma (ACS-Fall 2022) - "Several analogues related to CPP-115 were identified that do not inactivate GABA-AT but are potent inactivators of OAT. Enzyme inactivator design and mechanism studies will be discussed, as well as in vitro and in vivo efficacy and pharmacokinetic results, toxicology studies, and a clinical trial with CPP-115."

CNS Disorders • Epilepsy • Gastrointestinal Cancer • Hepatocellular Cancer • Neuralgia • Oncology • Pain • Solid Tumor

Rational Design, Synthesis, and Mechanism of (3S,4R)-3-Amino-4-(difluoromethyl)cyclopent-1-ene-1-carboxylic Acid: Employing a Second-Deprotonation Strategy for Selectivity of Human Ornithine Aminotransferase over GABA Aminotransferase. (PubMed, J Am Chem Soc) - "In this work, we first studied the inactivation mechanisms of hOAT by two well-known GABA-AT inactivators (CPP-115 and OV329)...Notably, the stopped-flow experiments were highly consistent with the proposed mechanism, suggesting a relatively slow hydrolysis rate for hOAT. The novel second-deprotonation mechanism of 10b contributes to its high potency and significantly enhanced selectivity for hOAT inhibition."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Theoretical and Mechanistic Validation of Global Kinetic Parameters of the Inactivation of GABA Aminotransferase by OV329 and CPP-115. (PubMed, ACS Chem Biol) - "The configurational entropy loss accounts for the difference in K values between the inactivators. The approach we describe in this work can be employed to determine the validity of globally derived parameters in the process of MBEI optimization for given inactivation mechanisms."

Clinical • Journal

A case report on the efficacy of vigabatrin analogue (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) in a patient with infantile spasms. (PubMed) - Epilepsy Behav Case Rep - "Here, we present a child treated with CPP-115 through an investigational new drug protocol who experienced a marked reduction of seizures with no evidence of retinal dysfunction. Given the potential consequences of ongoing infantile spasms and the limitations of available treatments, further assessment of CPP-115 is warranted."

Journal • Biosimilar • Epilepsy • Ophthalmology

Two-Dimensional Proton Magnetic Resonance Spectroscopy versus J-Editing for GABA Quantification in Human Brain: Insights from a GABA-Aminotransferase Inhibitor Study. (PubMed, Sci Rep) - "This clinical study is unique in that it involved chronic administration a GABA-amino transferase (AT) inhibitor (CPP-115), which induces substantial increases in brain GABA concentration, with normalization after washout...In general, GABA concentration changes detected using J-editing were closely mirrored by the 2D H MRS time courses. The data presented are particularly encouraging considering recent 2D H MRS methodological advances are continuing to improve temporal resolution and spatial coverage for achieving whole-brain, multi-metabolite mapping."

Journal