Key result
Clopidogrel and ticlopidine, prodrugs that irreversibly block the ADP P2Y12 receptor, likely could not be discovered or developed today due to their instability and complex metabolic profiles.
The historical discovery of clopidogrel and ticlopidine highlights that modern high-throughput screening and rational drug design might have missed these crucial prodrugs due to their unstable active metabolites.
Challenges modern high-throughput screening by suggesting key antiplatelet prodrugs would fail today; leaves open whether discovery criteria merit adjustment for metabolic complexity.
Clopidogrel and its predecessor, ticlopidine, are thienopyridine derivatives that inhibit platelet activation and aggregation by irreversibly blocking the ADP P2Y12 receptor. They are indicated for the reduction of atherothrombotic events in cardiovascular patients. Clopidogrel has a more favorable side effect profile than ticlopidine. These two molecules could not be discovered today through an in vitro high throughput screening because they are prodrugs, which must be transformed in the body into an active metabolite. The active metabolite is very unstable and cannot be obtained by chemical synthesis or stored. Moreover, its structure cannot be predicted by rational drug design. Even if these two prodrugs were discovered today by chance, they would probably not be developed by the majority of R&D teams because of a number of drawbacks associated with their strong metabolic transformation in the body and their irreversible effect on platelets.
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Jean‐Pierre Maffrand (2012) conducted a review in Cardiovascular disease. Clopidogrel and ticlopidine was evaluated. Clopidogrel and ticlopidine, prodrugs that irreversibly block the ADP P2Y12 receptor, likely could not be discovered or developed today due to their instability and complex metabolic profiles.
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