Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors.
Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65 microM, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.
Weber
A E
AE
Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Halgren
T A
TA
Doyle
J J
JJ
Lynch
R J
RJ
Siegl
P K
PK
Parsons
W H
WH
Greenlee
W J
WJ
Patchett
A A
AA
D000595:Amino Acid Sequence; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000092502:Renin Inhibitors