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  • Title: Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.
    Author: Bezençon O, Bur D, Weller T, Richard-Bildstein S, Remen L, Sifferlen T, Corminboeuf O, Grisostomi C, Boss C, Prade L, Delahaye S, Treiber A, Strickner P, Binkert C, Hess P, Steiner B, Fischli W.
    Journal: J Med Chem; 2009 Jun 25; 52(12):3689-702. PubMed ID: 19358611.
    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.
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