Tremendous resources have been devoted to the design of orally efficacious renin inhibitors, starting in the late 1970s [17-20], and a vast number of potent and selective peptide-like TSM inhibitors have been reported. Several candidates progressed into the clinic but suffered from poor intestinal absorption or high liver first-pass elimination, high synthetic complexity and hence high cost of goods, and/or insufficient clinical efficacy. The renin drug discovery project at Ciba-Geigy started in 1980 and transitioned through the evolution over three generations of renin inhibitors, ranging from modified linear peptides initially, to more drug-like peptidomimetics and ultimately to completely novel chemical structures that still function as TSM inhibitors. Computer-aided molecular modeling along with X-ray crystallography of human renin with and without bound inhibitors enabled us to adopt a systematic direct target-structure based strategy. This eventually culminated in the discovery of aliskiren, 1, representing a unique class of topological peptidomimetic renin inhibitors, as described in more detail by this review.
The large peptide inhibitor CGP29287, 2 (Figure 2), derived from the N-terminal sequence of angiotensinogen by incorporation of the statine TSM at the renin cleavage site and with modification of both N- and C-terminal sites, was the first proteolytically stable, long-acting renin inhibitor shown to be active after intravenous and oral administration to monkeys . Although not considered 'drug-like' due to its peptide characteristics, this first-generation inhibitor proved its importance as a pharmacological tool for studying the endocrine, hemodynamic, renal and cardiac responses to tissue and systemic renin inhibition in vivo in primates . Subsequently, reduction of molecular size by truncation at both the N- and the C-terminus and incorporation of a hydroxyethylene
Figure 2 First generation peptide renin inhibitor — CGP29287 (2).
Figure 3 Second-generation peptide-based renin inhibitors.
(HE) isostere provided inhibitors spanning the S4-S2' enzyme recognition sites. Further structure refinement identified CGP38560, 3 (Figure 3) , a renin inhibitor of the second generation and the first selected at Ciba-Geigy for clinical investigations. This potent and selective inhibitor of human and marmoset plasma renin in vitro (IC50 = 0.7nM) reduced mean arterial pressure (MAP) and suppressed PRA in Na-depleted restrained marmosets (10mg/kg oral dose) . Owing to its short duration of action in hypertensive patients and low (<1%) oral bioavailability in humans, 3 was not considered to be a clinically viable drug [24,25].
Remikiren (RO-42-5892, 4), with a plasma human renin IC50 = 0.8 nM, combined the N-terminal tert-butylsulfonyl of 3 with a shorter C-terminal diol TSM  and was investigated by Hoffmann-La Roche in phase II trials. RO-42-5892 caused significant BP lowering in hypertensive patients, but antihypertensive responses were only short-lasting at the maximal tolerated dose . Oral bioavailability of 4 was low in monkeys, rats, dogs and humans (~ 1%) due to rapid liver first-pass metabolism and biliary excretion of unchanged drug [27,28]. It is noteworthy that 4 was proposed to act primarily by inhibiting an extra-plasma renin pool . RO-42-5892 is the first renin inhibitor for which extensive partitioning to, and retention by, the kidney has been reported .
More water soluble second generation inhibitors with superior pharmacokinetics in animal species were subsequently disclosed. SC-56525, 5 (IC50 = 1.2 nM), was reported by Searle to exert potent oral BP lowering effects in both Na-depleted and renal hypertensive dogs . Oral bioavailability of 5 was 66% in dogs (30mg/kg po); however, nonlinear pharmacokinetics and a short elimination half-life (1.3 h) were observed . Zankiren (A-72517, 6, IC50 = 1.1 nM) culminated from a structure-oral absorption optimization strategy at Abbott [7,32-34]. Oral bioavailability in cynomolgus monkey, dog and rat was 8, 53 and 24%, respectively, with the dog predicting best the human bioavailability . Remarkably, distribution studies in animals showed selective uptake of 6 into the kidneys, which could explain its favorable effects on renal hemodynamics . In patients, 6 showed rapid oral absorption and significant antihypertensive efficacy . Zankiren has been considered a hallmark second-generation renin inhibitor, although the drug was not developed further .
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