Novel imidazol-1-ylmethyl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-ones as potent and selective CYP11B1 inhibitors for the treatment of Cushing's syndrome.
CYP11B1 inhibition is a promising therapy for Cushing's syndrome. Starting from etomidate, references I and II, the title compounds were designed and synthesized. Cyclopropyl analogue 4 was identified as a CYP11B1 inhibitor more potent (IC(50) = 2.2 nM) than leads and more selective (SF = 11) than I and metyrapone. Since it also showed potent inhibition of rat CYP11B1 and good selectivity over human CYP17 and CYP19, it is a promising candidate for further development.
Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2-3, D-66123 Saarbrücken, Germany.
Lina
L
Yin
Simon
S
Lucas
Frauke
F
Maurer
Uli
U
Kazmaier
Qingzhong
Q
Hu
Rolf W
RW
Hartmann
D000818:Animals; D001141:Aromatase / Q000378:metabolism; D003480:Cushing Syndrome / Q000188:drug therapy*; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013237:Stereoisomerism; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D007093:Imidazoles; D015363:Quinolones; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase