Synthetic inhibitors of elastase

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Decades of research focused on developing inhibitors for human neutrophil elastase (HNE).
• Significant advancements in creating potent reversible peptidic inhibitors with dissociation constants in the 10(-11) M range.
• Development of heterocyclic inhibitors balancing reactivity, stability, and enzyme-inhibitor adduct stability.

Purpose of the Study:

• To identify therapeutic agents for diseases associated with HNE.
• To evaluate the in vivo efficacy of HNE inhibitors in animal models.
• To identify a clinically suitable HNE inhibitor with desirable drug properties.

Main Methods:

• Design and synthesis of low molecular-weight peptidic and heterocyclic HNE inhibitors.
• Evaluation of inhibitor potency using dissociation constants.
• Assessment of in vitro and in vivo activity, chemical stability, metabolic stability, and toxicity in animal models.

Main Results:

• Identification of extremely potent reversible peptidic inhibitors (dissociation constants ~10(-11) M).
• Successful strategies for heterocyclic inhibitors addressing reactivity and stability challenges.
• Demonstration of in vivo efficacy for several compounds via various administration routes in animal models.
• ICI 200,880 exhibits chemical stability, in vitro/in vivo activity, long duration of action, and adequate metabolic stability.

Conclusions:

• ICI 200,880 possesses key characteristics for treating HNE-associated diseases.
• ICI 200,880 is the sole low molecular-weight HNE inhibitor currently in clinical trials.
• ICI 200,880 may establish the clinical utility of synthetic HNE inhibitors.