Scientific Background | BPP-9a occupies a specific place in drug history: the supplied sequence, a pyroglutamyl nonapeptide, is that of teprotide (SQ 20,881), the compound that carried the bradykinin-potentiating peptides out of snake venom pharmacology and into the clinic. Teprotide lowered blood pressure in patients and established that inhibiting angiotensin-converting enzyme was a viable therapeutic strategy, but it had to be given intravenously because, as a peptide, it was not orally active. That limitation is what prompted the work that followed. Cushman and Ondetti's account of the design of captopril describes how the structural features responsible for this nonapeptide's inhibitory activity, in particular the C-terminal proline, were abstracted into a small molecule that retained the activity while surviving oral administration. Captopril and the ACE inhibitor class that followed are therefore direct descendants of this sequence, which makes it one of the more frequently cited worked examples of natural-product-led drug design. As a research reagent it remains a genuine ACE inhibitor rather than a historical curiosity. It is used as a peptide-class comparator against small molecule inhibitors, in studies of the two catalytic domains of somatic ACE, which members of this series inhibit with differing site specificity, and in bradykinin potentiation experiments. For the shorter member of the series with reported nitric-oxide-dependent activity, see BPP-5a (LT1138). |
References | 1. Cushman DW, Ondetti MA. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension (1991) 17:589. Hypertension 1991;17:589 2. Teprotide (SQ 20,881) — pharmacology overview. Teprotide overview 3. The bradykinin-potentiating peptides from venom gland and brain of Bothrops jararaca contain highly site specific inhibitors of the somatic angiotensin-converting enzyme. Toxicon (2005). Toxicon 2005 4. Discovery and development of ACE inhibitors — overview. ACE inhibitor development |
