PI-301 / Pantherics - LARVOL DELTA

Benzodiazepines Limit Murine Allergic Lung Inflammation Potentially by Inhibiting Lymphocyte Store-operated Calcium Entry Via Modulation of the Mitochondrial Sodium Calcium Exchanger (ATS 2024) - "During continuous fluorescence detection, SOCE was induced in 0mM calcium buffer with thapsigargin, an irreversible inhibitor of SR/ER Ca2+ ATPase (SERCA), followed by the introduction of 2mM of extracellular Ca2+. MIDD0301, a novel benzodiazepine without CNS effects, limits lung inflammation in an in vivo murine model. Both diazepam and CGP37517 were shown to inhibit SOCE at similar levels, suggesting that benzodiazepines may inhibit immune cell activation by hindering normal mitochondrial calcium fluxes in a NCLX-dependent manner. Given its anti-inflammatory effects on non-neuronal cells, benzodiazepines are promising as novel therapeutics in allergic lung inflammation and other inflammatory diseases."

Preclinical • Inflammation • Pneumonia • IL4

Design, Synthesis, and Biological Evaluation of Novel Spiro Imidazobenzodiazepines to Identify Improved Inhaled Bronchodilators. (PubMed, J Med Chem) - "Novel gamma-aminobutyric acid receptor (GABAR) ligands structurally related to imidazobenzodiazepine MIDD0301 were synthesized using spiro-amino acid N-carboxyanhydrides (NCAs)...Pharmacological activities at lung GABARs were demonstrated by ex vivo relaxation of guinea pig airway smooth muscle and reduction of methacholine-induced airway hyperresponsiveness (AHR) in conscious mice. We identified bronchodilator 5c with an affinity of 9 nM for GABARs that was metabolically stable in the presence of human and mouse microsomes."

Journal

Synthesis, biological evaluation, and molecular modeling of novel imidazobenzodiazepines to identify lead compounds for the oral treatment of asthma (ACS-Sp 2023) - "A novel synthetic strategy was employed to synthesize compounds structurally related to asthma drug candidate MIDD0301...A relationship between the reduction of airway hyperresponsiveness and GABAAR binding was observed. A similar structure-activity relationship was observed for airway smooth muscle relaxation using ex vivo Guinea pig tracheal rings in response substance P"

Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Synthesis and evaluation of disubstituted imidazodiazepines using a novel synthetic strategy to generate compounds with potential application as an orally available asthma medication | Poster Board #2772 (ACS-Fall 2022) - "New compounds structurally related to asthma drug candidate MIDD0301 have been synthesized using a novel synthetic route with various amino acid N-carboxyanhydrides (NCAs)...Solubility, permeability, and toxicity of the newly generated imidazodiazepines has been determined. Current investigations evaluate the affinity of the compounds towards gamma aminobutyric acid A receptors, tissue selectivity, and the ability to relax airway smooth muscle."

Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer. (PubMed, Drug Dev Res) - "In mouse blood, the taurine adduct was only observed for MIDD0301. Overall, both compounds exhibited similar receptor binding and pharmacodynamic properties with subtle differences in metabolism and greater oral availability and blood concentrations of MIDD0301S."

Journal • PK/PD data • Asthma • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • IFNG

Development of Inhaled GABA Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders. (PubMed, ACS Pharmacol Transl Sci) - "We report the modification of MIDD0301, an imidazodiazepine GABA receptor (GABAR) ligand, using two alkyl substituents. We developed PI310 with a 6-(4-phenylbutoxy)hexyl chain as used in the long-acting β2-agonist salmeterol and PI320 with a poly(ethylene glycol) chain as used to improve the brain:plasma ratio of naloxegol, a naloxone analogue. Both imidazodiazepines showed affinity toward the GABAR binding site of clonazepam, with IC values of 576 and 242 nM, respectively...Overall, PI320 is a promising inhaled drug candidate to quickly relax airway smooth muscle in bronchoconstrictive disorders, such as asthma. Future studies will evaluate the pharmacokinetic/pharmacodynamic properties of PI320 when administered orally."

Journal • Asthma • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

Identification and Quantification of MIDD0301 metabolites. (PubMed, Curr Drug Metab) - "MIDD0301 undergoes no phase I and moderate phase II metabolism."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Nebulized MIDD0301 is Efficacious in Allergic and Microbial Lung Inflammation Models (AAAAI 2021) - "MIDD0301 improved inflammation and lung function in LPS/INFγ and poly(I:C) challenged mice with acute and chronic nebulization. No respiratory or CNS toxicities were demonstrated at 50x the therapeutic nebulized dose.  Conclusions MIDD0301 is a promising NCE that, following nebulized administration, safely reduces AHR and inflammation in allergic murine asthma models and is further efficacious in reducing inflammatory sequelae of bacterial and viral lung infections."

Asthma • Immunology • Inflammation • Pneumonia • Respiratory Diseases

Nebulized MIDD0301 Reduces Airway Hyperresponsiveness in Moderate and Severe Murine Asthma Models. (PubMed, ACS Pharmacol Transl Sci) - "Oral dexamethasone was ineffective in this model. In addition, no adverse cardiovascular effects were observed following 100 mg/kg i.p. dosing. These results further demonstrate that charged imidazodiazepine MIDD0301 can selectively target lung GABAR without adverse motor, cardiovascular, or respiratory effects and inhaled dosing is effective in reducing bronchoconstriction in allergen and infectious lung inflammation."

Journal • Preclinical • Asthma • Cardiovascular • CNS Disorders • Depression • Immunology • Inflammation • Pneumonia • Psychiatry • Respiratory Diseases • IFNG