Spiro-Azetidine Oxindoles as Long-Acting Injectables for Pre-Exposure Prophylaxis against Respiratory Syncytial Virus Infections
J. Med. Chem. 2024, 67, 10986
Long-acting injectable (LAI) drugs, which you would expect to display efficacious plasma levels over a period of several months from 1-2 doses, have seen interest lately in numerous fields.[doi.org/10.1016/j.ebiom.2023.104764, doi.org/10.1038/s41578-021-00405-w, doi.org/10.1080/17425247.2022.2106213] This represents a significant divergence from classical med chem assumptions, where drug effect and clearance both occur in relatively short periods (hours up to days). If a desired effect is to be sustained, and the drug has a “normal” rate of clearance, repeat doses must be given to maintain blood plasma levels. This can be impacted massively by patient noncompliance, leading to inconsistent use and treatment failure, leading to the frequently targeted “UID” (unum in diem = once a day) dosing regimen, in the hope that this will lead to the best possible patient compliance outcome.
One such application for these LAI products, is in pre-exposure prophylactic treatments against viral infections. This serves the medical need, unmet by vaccines or monoclonal antibodies (mAbs), of immunocompromised/ immunosenescent patients and paediatric patients too young for mAb treatments.
So how is it achieved? In this paper, researchers from Janssen Pharmaceuticals define their guiding principles and strategy for delivering a long-acting pre-exposure prophylactic antiviral agent for RSV infection. Firstly, the potency vs the target must be as high as possible and the in-vivo clearance must be low, as is the goal for any med chem project, to bring down the definition of “efficacious blood levels”, and hence the projected human dose. The authors sought an injectable crystalline suspension as their preferred formulation, where the API would display low solubility and high crystallinity (to keep the particle size low), leading to very slow dissolution.
Figure 1: Structure 7KQD, literature inhibitor RV521 bound to the RSV fusion protein
The starting point was a spiro-oxindole scaffold, that is common among numerous disclosed RSV fusion inhibitors, [WO2014060411, WO2015158653] displaying sub-nanomolar efficacy. The authors identified a sub-series of this chemotype that included a spiro-azetidine ring with different polar capping groups, which offered a route to obtain compounds in the property space required for LAI dosing:
- High potency
- Low clearance
- High logD
- Low solubility
This goal was made further achievable by modification of the long alkyl chain on the benzimidazole, which usually points to solvent (Figure 1), and can be used to modulate properties without affecting potency too much.
With this, the authors ended up with a small family of compounds to take forward for in-vivo studies. 12 week PK studies were undertaken in rats and dogs as single intramuscular (IM) injections, where parameters such as the injection site release rate (ka) and the % dose released over 12 weeks (F12w) were determined. The candidate distinguished itself with exceptional clearance/release rates over the tested period. While it remains tricky to correlate changes in molecular properties to injection site release rate, large differences in the latter were observed alongside changes in logD and aqueous solubility. A general trend of slower release with higher logD and/or lower solubility was noted.
PK/PD studies carried out in BALB/c mice and cotton rats revealed that the PD response was driven by the plasma concentration at the time of infection. This is characteristic of virus entry / fusion inhibitors, and outlines an important principle to bear in mind for prophylactic treatments, where protection against infection is expected at any point during the course of efficacy.
The targeted blood level, based on cellular efficacy measurements and other IVIVE approaches was just 34 ng mL-1. This lead to a projected human dose of 200 mg as a single IM/SC injection of the API as a microsuspension, to provide cover for at least 3 months!
