Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors: influence of heteroaryl derivatization on potency and selectivity.
Recently, we reported on the development of potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis. A major drawback of these nonsteroidal compounds was a strong inhibition of the hepatic drug-metabolizing enzyme CYP1A2. In the present study, we examined the influence of substituents in the heterocycle of lead structures with a naphthalene molecular scaffold to overcome this unwanted side effect. With respect to CYP11B2 inhibition, some substituents induced a dramatic increase in inhibitory potency. The methoxyalkyl derivatives 22 and 26 are the most potent CYP11B2 inhibitors up to now (IC50 = 0.2 nM). Most compounds also clearly discriminated between CYP11B2 and CYP11B1, and the CYP1A2 potency significantly decreased in some cases (e.g., isoquinoline derivative 30 displayed only 6% CYP1A2 inhibition at 2 microM concentration). Furthermore, isoquinoline derivative 28 proved to be capable of passing the gastrointestinal tract and reached the general circulation after peroral administration to male Wistar rats.
Heim
Ralf
R
Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbrucken, Germany.
Lucas
Simon
S
Grombein
Cornelia M
CM
Ries
Christina
C
Schewe
Katarzyna E
KE
Negri
Matthias
M
Müller-Vieira
Ursula
U
Birk
Barbara
B
Hartmann
Rolf W
RW
D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D019388:Cytochrome P-450 CYP1A2; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D005355:Fibrosis / Q000188:drug therapy; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D008297:Male; D009206:Myocardium / Q000473:pathology; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D009281:Naphthalenes; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D019405:Cytochrome P-450 CYP11B2