Design and Preparation of Potent, Nonpeptidic, Bioavailable Renin Inhibitors

Abstract

Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.

Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation

“…This trend can be explained based on the fact that most reported potent renin inhibitors (including those in our training list) tend to have large molecular sizes Table 6 The training compounds used for adding excluded spheres for Hypo1/5 and Hypo1/7 using HIPHOP-REFINE module of CATALYST. (of MW > 600) [16,18,7,19,[63][64][65] and therefore require wellbalanced combination of hydrophobic and hydrophilic groups. Lack of such balance for such large molecules can lead to excessive hydration at one end, or poor water-solubility at the other, which in both cases seem to undermine their affinities to renin.…”

“…Earlier renin inhibitors were mainly peptidomemtic [7,8]. However, the unfavorable pharmacokinetic behavior of peptidomemtic inhibitors prompted continuous efforts towards developing nonpeptidic renin inhibitors.…”

Pharmacokinetics, Pharmacodynamics, and Tolerability of ACT-077825, a New Direct Renin Inhibitor After Multiple-ascending Doses in Healthy Subjects

“…[2][3][4][5][6] Because renin is responsible for the cleavage of angiotensinogen into angiotensin I (ANGI), its direct inhibition blocks the RAAS at its first and rate-limiting step and compensates for the reactive increase in renin release and activity 7,8 induced by the disruption of the negative feedback loop exerted by ANGII as observed after treatment with ACEIs and ANGII receptor blockers. 8,9 Until now, aliskiren, a highly potent peptidomimetic direct RI, 10,11 remains the only nonpeptide and low-molecular weight orally active RI approved by the US Food and Drug Administration (Tekturna) and European Medicines Agency (EMA) (Rasilez) for the treatment of hypertension. 3,7,11 Despite its low oral absolute bioavailability of approximately 3%, aliskiren was effective in lowering blood pressure in patients with mild-to-moderate hypertension.…”

Development and Validation of a Robust QSAR Model For Piperazine and Keto Piperazine Derivatives as Renin Inhibitors

“…More recently, a novel series of renin inhibitors based on the 3, 9-diazabicyclo nonene have been developed [12]. The piperazine and keto piperazine derivatives have been found to be potent, efficacious, oral and good bioavailable renin inhibitors [11,13,14].…”