Synthesis and evaluation of inhibitors of cytochrome P450 3A (CYP3A) for pharmacokinetic enhancement of drugs.
The HIV protease inhibitor ritonavir (RTV) is also a potent inhibitor of the metabolizing enzyme cytochrome P450 3A (CYP3A) and is clinically useful in HIV therapy in its ability to enhance human plasma levels of other HIV protease inhibitors (PIs). A novel series of CYP3A inhibitors was designed around the structural elements of RTV believed to be important to CYP3A inhibition, with general design features being the attachment of groups that mimic the P2-P3 segment of RTV to a soluble core. Several analogs were found to strongly enhance plasma levels of lopinavir (LPV), including 8, which compares favorably with RTV in the same model. Interestingly, an inverse correlation between in vitro inhibition of CYP3A and elevation of LPV was observed. The compounds described in this study may be useful for enhancing the pharmacokinetics of drugs that are metabolized by CYP3A.
Flentge
Charles A
CA
Abbott Laboratories, Departments of Antiviral Research (D-R4CQ), Building AP-52, 200 Abbott Park Road, Abbott Park, IL 60064-3537, USA. chuck.a.flentge@abbott.com
Randolph
John T
JT
Huang
Peggy P
PP
Klein
Larry L
LL
Marsh
Kennan C
KC
Harlan
John E
JE
Kempf
Dale J
DJ
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D015195:Drug Design; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061466:Lopinavir; D011744:Pyrimidinones / Q000097:blood*; D019438:Ritonavir / Q000031:analogs & derivatives / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir