Mdl 101,146
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Summary
MDL 101,146 is a synthetic peptidyl electrophilic ketone that acts as a potent, reversible inhibitor of human neutrophil elastase (HNE). Developed in the 1990s, it has been evaluated in a range of rodent models of inflammatory disease, including collagen‑induced arthritis and HNE‑triggered acute lung injury. The compound is not known to have any regulatory approval and its clinical use remains experimental.
Mechanism of Action
MDL 101,146 binds to the active site of neutrophil elastase, a serine protease that degrades extracellular‑matrix proteins such as elastin and proteoglycans. In vitro studies report a Ki of about 25 nM, indicating high affinity. By blocking HNE, the compound prevents proteolytic cleavage of connective‑tissue substrates, thereby reducing tissue damage associated with excessive elastase activity.
What the Research Shows
Pre‑clinical work shows that MDL 101,146 inhibits HNE‑mediated degradation of proteoglycan and elastin in vitro. In rodents, oral dosing (10–50 mg kg⁻¹) prevented HNE‑induced pulmonary hemorrhage, with an ED50 of ~15 mg kg⁻¹ and a duration of action of 2–4 h. Intravenous (0.5 mg kg⁻¹) and intratracheal (≈5 µg kg⁻¹) administration also reduced hemorrhage, the latter lasting 6–18 h. In a rat collagen‑induced arthritis model, oral MDL 101,146 lowered clinical scores, joint swelling, and cartilage destruction. Pharmacokinetic data indicate that the compound is metabolically stable in rat liver homogenates and is absorbed from the gut, though absorption varies among analogues. No human trials have been reported.
Reported Benefits
Animal studies suggest that MDL 101,146 can protect connective tissue from elastase‑driven damage, lessen cartilage loss in experimental arthritis, and attenuate acute lung injury caused by HNE. These effects point to potential therapeutic value in diseases where neutrophil elastase contributes to pathology, such as certain inflammatory joint disorders and acute pulmonary insults.
Limitations of the Evidence
All evidence is confined to in‑vitro assays and acute or sub‑acute rodent models; no human safety or efficacy data exist. The duration of enzymatic inhibition is relatively short, and the compound’s effectiveness in chronic disease settings is unknown. Comparative studies with other elastase inhibitors are limited, and the lack of regulatory status means it is not available for clinical use.
Safety Considerations
Pre‑clinical reports did not describe overt toxicity at effective doses, but comprehensive safety assessments are absent. The specificity for HNE over other proteases was demonstrated in animal models, yet off‑target effects have not been explored in depth. Because human pharmacology and toxicology have not been reported, the safety profile remains uncertain.
How It Is Administered
MDL 101,146 has been administered to rodents by oral gavage, intravenous bolus injection, and intratracheal instillation. Effective oral doses ranged from 10 to 50 mg kg⁻¹, while intravenous efficacy was observed at 0.5 mg kg⁻¹ and intratracheal at ≈5 µg kg⁻¹. Formulation details were not provided in the abstracts.
Routes of Administration
No administration routes recorded yet.
Goals & Uses
No goal associations recorded yet.
Contraindications
No contraindications recorded yet.
Adverse Effects
No adverse effects recorded yet.
Drug Interactions
No drug interactions recorded yet.
Population Constraints
No population constraints recorded yet.
Regulatory Status
No regulatory status recorded yet.
Evidence & Sources
- Journal ArticleLowJanusz MJ, Durham SL1997-01-01T00:00:00.000000Z
- Journal ArticleLowDurham SL, et al.1994-01-01T00:00:00.000000Z
- Journal ArticleLowJanusz MJ, Hare M1994-01-01T00:00:00.000000Z
- Journal ArticleLowAngelastro MR, et al.1994-01-01T00:00:00.000000Z
- Journal ArticleLowJanusz MJ, et al.1995-01-01T00:00:00.000000Z
Frequently Asked Questions
What type of compound is MDL 101,146?
It is a synthetic peptidyl electrophilic ketone designed to reversibly inhibit human neutrophil elastase, a serine protease involved in tissue degradation during inflammation.
How does MDL 101,146 work at the molecular level?
The molecule binds tightly to the active site of neutrophil elastase, blocking its ability to cleave extracellular‑matrix proteins. In vitro, it shows a Ki of about 25 nM, indicating high potency.
What disease models have been tested with MDL 101,146?
It has been studied in rodent models of collagen‑induced arthritis, where it reduced joint swelling and cartilage loss, and in HNE‑induced acute lung injury models, where it prevented pulmonary hemorrhage after oral, IV, or intratracheal dosing.
Has MDL 101,146 been evaluated in humans?
No. All published data are limited to in‑vitro experiments and animal studies. There are no clinical trial reports, safety data, or regulatory approvals for human use.
What is Mdl 101,146?
MDL 101,146 is a synthetic peptidyl electrophilic ketone that acts as a potent, reversible inhibitor of human neutrophil elastase (HNE). Developed in the 1990s, it has been evaluated in a range of rodent models of inflammatory disease, including collagen‑induced arthritis and HNE‑triggered acute lung injury. The compound is not known to have any regulatory approval and its clinical use remains experimental.