Addressing time-dependent CYP 3A4 inhibition observed in a novel series of substituted amino propanamide renin inhibitors, a case study.
Time-dependent inhibitors of CYPs have the potential to perpetrate drug-drug interactions in the clinical setting. After finding that several leading compounds in a novel series of substituted amino propanamide renin inhibitors inactivated CYP3A4 in an NADPH-dependent and time-dependent manner, a search to identify the cause of this liability was initiated. Extensive SAR revealed that the amide bridge present in compound 1 as a possible culprit. Through the installation of a metabolic soft spot distal to this moiety, potent renin inhibitors with improved CYP profile were identified.
Chen
Austin
A
Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada. austin_chen@merck.com
Dubé
Daniel
D
Dubé
Laurence
L
Gagné
Sébastien
S
Gallant
Michel
M
Gaudreault
Mireille
M
Grimm
Erich
E
Houle
Robert
R
Lacombe
Patrick
P
Laliberté
Sébastien
S
Liu
Suzanna
S
MacDonald
Dwight
D
Mackay
Bruce
B
Martin
David
D
McKay
Dan
D
Powell
David
D
Lévesque
Jean-François
JF
D000577:Amides / Q000737:chemistry; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011422:Propionates / Q000737:chemistry*; D000092502:Renin Inhibitors
D000577:Amides; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D011422:Propionates; D000092502:Renin Inhibitors; C510163:CYP3A4 protein, human