Abstract
Purpose :
Metadata analysis of Boehringer Ingelheim’s (BI) public database, opnMe, revealed the potential to repurpose BI-1915, a Cathepsin S inhibitor, for ophthalmic indications through ADMET Predictor® calculations of "rules of thumb" for topical ophthalmic drugs (ROx). This study aims to position BI-1915 as a potential ophthalmic therapeutic by utilizing in silico and in vitro data, to make predictive calculations for future validation in in vivo models.
Methods :
Initial literature review was performed to find association between the target protein and ophthalmic disease using following search inquiry on PubMed®: (Cathepsin S OR Cathepsin S*) AND (ocular OR eye OR ophthalmic OR "ocular tissue" or "eye compartment" or "eye tissue"). BI-1915 SMILES was inputted into ADMET Predictor and calculations were performed for "rules of thumb" for topical ophthalmic drugs (ROx) for optimal corneal permeability (CP), intrinsic solubility (IS), and adherence to ROx and Lipinski's Rule of 5 (RO5). These predictive calculations were transferred into GastroPlus® for further analysis, in an attempt to define meaningful boundaries in the pharmacokinetic and pharmacodynamic (PK/PD) profile of BI-1915 in both human and animal models.
Results :
Through literature analysis, BI-1915 was determined to have repositioning potential for dry eye disease. ROx compliance illustrated the potential for BI-1915 to be an optimal ophthalmic therapeutic, given balanced solubility & distribution coefficients at pH7.4, & high corneal permeability. Due to the lack of provided in vivo PK data for BI-1915, results from GastroPlus® OCAT are purely based on predictions, however indicate adequate PKPD exposure to cover the reported 17nM cathepsin S IC50 value.
Conclusions :
Target validation, predictive ROx calculations, and PBPK modeling of BI-1915 suggest that this novel cathepsin S inhibitor has potential for therapeutic repurposing in dry eye syndromes treatment. However, future experiments and in vivo data verification are required to validate if BI-1915 demonstrates reasonable ocular biopharmaceutics (dosing formulation and adequate PK options). BI-1915 demonstrates adherence to ROx using in silico methods and available in vitro data.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.