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Published on: April 4, 2019
Spiro-Azetidine Oxindoles as Long-Acting Injectables for Pre-Exposure Prophylaxis against Respiratory Syncytial Virus
Bart Kesteleyn1, Florence Herschke1, Nicolas Darville1
1Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium.
Insights
New small molecules, spiro-azetidine oxindoles, show potential for preventing respiratory syncytial virus (RSV) in immunocompromised individuals. These compounds offer long-acting protection for 3-6 months after one or two injections.
Area of Science:
- Virology
- Immunology
- Medicinal Chemistry
Background:
- Respiratory syncytial virus (RSV) significantly impacts vulnerable populations, including infants, the elderly, and immunocompromised individuals, leading to substantial hospitalizations.
- Current preventive measures like monoclonal antibodies and vaccines primarily target infants and the elderly, leaving a critical gap for immunocompromised patients.
- There is an unmet need for effective strategies to prevent RSV disease in immunocompromised individuals.
Purpose of the Study:
- To develop novel small molecule inhibitors targeting RSV entry.
- To evaluate the potency and pharmacokinetic properties of spiro-azetidine oxindoles as potential RSV therapeutics.
- To assess the feasibility of long-acting formulations for sustained RSV protection in immunocompromised populations.
Main Methods:
- Synthesis and characterization of spiro-azetidine oxindoles.
- In vitro assessment of RSV entry inhibition.
- Evaluation of developability attributes and pharmacokinetic profiles.
- Formulation development for long-acting intramuscular (IM) or subcutaneous (SC) injections.
Main Results:
- Spiro-azetidine oxindoles demonstrated potent inhibition of RSV entry.
- These compounds exhibited favorable developability characteristics.
- Long-acting pharmacokinetic profiles were achieved with aqueous suspension formulations.
- Potential for 3- to 6-month protection with 1-2 IM or SC injections was suggested.
Conclusions:
- Spiro-azetidine oxindoles represent a promising class of small molecule RSV entry inhibitors.
- Long-acting formulations offer a potential strategy for sustained RSV prevention in immunocompromised patients.
- These findings may lead to new options for managing RSV complications in high-risk populations.
Abstract:
Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.
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