Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy.
A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development.
Simoneau
B
B
Boehringer Ingelheim (Canada) Ltd., Bio-Méga Research Division, Laval, Québec. bsimoneau@bio-mega.boehringer-ingelheim.ca
Lavallée
P
P
Anderson
P C
PC
Bailey
M
M
Bantle
G
G
Berthiaume
S
S
Chabot
C
C
Fazal
G
G
Halmos
T
T
Ogilvie
W W
WW
Poupart
M A
MA
Thavonekham
B
B
Xin
Z
Z
Thibeault
D
D
Bolger
G
G
Panzenbeck
M
M
Winquist
R
R
Jung
G L
GL
D000284:Administration, Oral; D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D006801:Humans; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D012083:Renin / Q000097:blood; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000577:Amides; D012083:Renin; D000092502:Renin Inhibitors