Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics
Research article published in Journal of medicinal chemistry (2002)
Abstract
Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED(50) was 5.4 nmol/kg.min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Summary
Peer-reviewed research on therapeutic compound development relevant to leech-derived anticoagulants and antithrombotic agents. Indexed in PubMed and verified against the NCBI record.
Why This Matters for Hirudotherapy
This medicinal-chemistry study synthesized peptide transition-state-analogue thrombin inhibitors and found that adjusting overall charge distribution could yield an orally bioavailable compound (compound 27) with a thrombin inhibition constant of 1.1 nM and oral bioavailability of 32% in rats and 71% in dogs, plus in vivo antithrombotic efficacy. It connects to the ASH story because thrombin is the precise target of hirudin, the leech secretome's flagship anticoagulant, so this work reflects the broader pharmaceutical effort to convert potent thrombin inhibition into orally available drugs of the kind leech biology helped inspire. Caveat: the abstract makes no mention of leeches or hirudin and reports only preclinical rat/dog pharmacokinetic and animal-model data, so it is relevant as thrombin-inhibitor drug-discovery context, not as clinical or leech-specific evidence.
Citation
Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics.
Adang AE et al. · Journal of medicinal chemistry, 2002
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