Ketopiperazine-based renin inhibitors: optimization of the "C" ring.
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
Pfizer Global Research and Development, Michigan Laboratories, Department of Chemistry, Ann Arbor, MI 48105, USA. Daniel.Holsworth@pfizer.com
Daniel D
DD
Holsworth
Cuiman
C
Cai
Xue-Min
XM
Cheng
Wayne L
WL
Cody
Dennis M
DM
Downing
Noe
N
Erasga
Chitase
C
Lee
Noel A
NA
Powell
Jeremy J
JJ
Edmunds
Michael
M
Stier
Mehran
M
Jalaie
Erli
E
Zhang
Pat
P
McConnell
Michael J
MJ
Ryan
John
J
Bryant
Tingsheng
T
Li
Aparna
A
Kasani
Eric
E
Hall
Rajendra
R
Subedi
Mohammad
M
Rahim
Samarendra
S
Maiti
D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors; D010879:Piperazines; D000092502:Renin Inhibitors; C104464:CYP3A protein, human; C510163:CYP3A4 protein, human