Discovery of inhibitors of human renin with high oral bioavailability.
Knowledge of the sequence of a bioactive protein (angiotensinogen) and the availability of a natural product inhibitor lead (pepstatin) were the starting point for discovery of potent penta- and hexapeptide renin inhibitors. Study of the metabolism and disposition of these substances forced the discovery of simpler inhibitors leading to the discovery of oral activity in Terlakiren (22). Modification of physical properties led to the synthesis of aminopiperidine 30, which was identified by oral efficacy profiling. Structural modification to give enzymatic stability produced the bioavailable benzylsuccinate inhibitor 34. Its bioactive monomethylamine metabolite (35, CP-108,671) was subsequently found to have uniformly high oral bioavailability and activity in various species including primates.
Department of Medicinal Chemistry, Pfizer Inc, Groton, CT 06340, USA.
D J
DJ
Hoover
B A
BA
Lefker
R L
RL
Rosati
R T
RT
Wester
E F
EF
Kleinman
J S
JS
Bindra
W F
WF
Holt
W R
WR
Murphy
M L
ML
Mangiapane
G M
GM
Hockel
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000614:Aminocaproates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011487:Protein Conformation; D012083:Renin / Q000097:blood / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000614:Aminocaproates; D002918:Chymotrypsin; D009842:Oligopeptides; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors; C034495:3-amino-2-hydroxy-5-methylhexanoic acid