title: Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors: influence of heteroaryl derivatization on potency and selectivity.
abstract: 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.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbrucken, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Heim
authors.forename: Simon
authors.initials: S
authors.lastname: Lucas
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Grombein
authors.forename: Christina
authors.initials: C
authors.lastname: Ries
authors.forename: Katarzyna E
authors.initials: KE
authors.lastname: Schewe
authors.forename: Matthias
authors.initials: M
authors.lastname: Negri
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller-Vieira
authors.forename: Barbara
authors.initials: B
authors.lastname: Birk
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: 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
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D009281:Naphthalenes; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D019405:Cytochrome P-450 CYP11B2