A novel class of oral direct renin inhibitors: highly potent 3,5-disubstituted piperidines bearing a tricyclic p3-p1 pharmacophore.
A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.
Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
Nils
N
Ostermann
Simon
S
Ruedisser
Claus
C
Ehrhardt
Werner
W
Breitenstein
Andreas
A
Marzinzik
Edgar
E
Jacoby
Eric
E
Vangrevelinghe
Johannes
J
Ottl
Martin
M
Klumpp
J Constanze D
JC
Hartwieg
Frederic
F
Cumin
Ulrich
U
Hassiepen
Jörg
J
Trappe
Richard
R
Sedrani
Sabine
S
Geisse
Bernd
B
Gerhartz
Paul
P
Richert
Eric
E
Francotte
Trixie
T
Wagner
Markus
M
Krömer
Takatoshi
T
Kosaka
Randy L
RL
Webb
Dean F
DF
Rigel
Jürgen
J
Maibaum
Daniel K
DK
Baeschlin
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D012083:Renin / Q000737:chemistry; D000092502:Renin Inhibitors
D010880:Piperidines; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors