Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.
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.
Drug Discovery and Preclinical Research, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. olivier.bezencon@actelion.com
Olivier
O
Bezençon
Daniel
D
Bur
Thomas
T
Weller
Sylvia
S
Richard-Bildstein
Lubos
L
Remen
Thierry
T
Sifferlen
Olivier
O
Corminboeuf
Corinna
C
Grisostomi
Christoph
C
Boss
Lars
L
Prade
Stéphane
S
Delahaye
Alexander
A
Treiber
Panja
P
Strickner
Christoph
C
Binkert
Patrick
P
Hess
Beat
B
Steiner
Walter
W
Fischli
D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D053961:Azabicyclo Compounds; D004791:Enzyme Inhibitors; D000092502:Renin Inhibitors