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Orally active peptidomimetic RGD analogs that are glycoprotein IIb/IIIa antagonists.
W Wang1, R T Borchardt, B Wang
1Department of Chemistry, North Carolina State University, Raleigh, NC 27695, USA.
Current Medicinal Chemistry
|March 7, 2000
Summary
Orally active Arg-Gly-Asp (RGD) analogs targeting glycoprotein IIb/IIIa show promise for treating heart conditions. Strategies like prodrugs and constrained designs enhance their oral bioavailability and therapeutic potential.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cardiovascular Research
Background:
- Peptidomimetic Arg-Gly-Asp (RGD) analogs inhibit platelet aggregation by targeting glycoprotein IIb/IIIa.
- RGD analogs are potential treatments for unstable angina and myocardial infarction.
- Low oral bioavailability due to poor membrane permeability and metabolic instability hinders clinical development.
Purpose of the Study:
- To review recent advancements in developing orally active RGD analogs.
- To discuss strategies for improving oral bioavailability of RGD analogs.
- To highlight lessons learned for future peptidomimetic drug design.
Main Methods:
- Modifications to enhance metabolic stability, including N-alkylation and C-terminal modifications.
- Prodrug strategies (simple ester, double, triple, cyclic) to improve membrane permeability.
- De novo design of centrally constrained RGD analogs for enhanced oral bioavailability.
Main Results:
- N-alkylation and C-terminal modifications improved metabolic stability of RGD analogs.
- Prodrug approaches significantly enhanced membrane permeability and oral activity.
- Centrally constrained RGD analogs demonstrated improved oral bioavailability while retaining potency.
Conclusions:
- Significant progress has been made in developing orally active RGD analogs.
- Prodrugs and constrained designs are effective strategies for improving RGD analog oral bioavailability.
- Findings offer valuable insights for designing other orally bioavailable peptidomimetic drugs.