Journal of Medicinal Chemistry p. 3689 - 3702 (2009)
Update date:2022-07-30
Topics:
Bezen?on, Olivier
Bur, Daniel
Weller, Thomas
Richard-Bildstein, Sylvia
Remeň, Lubo?
Sifferlen, Thierry
Corminboeuf, Olivier
Grisostomi, Corinna
Boss, Christoph
Prade, Lars
Delahaye, Stéphane
Treiber, Alexander
Strickner, Panja
Binkert, Christoph
Hess, Patrick
Steiner, Beat
Fischli, Walter
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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