title: Tetrahydropyrroloquinolinone type dual inhibitors of aromatase/aldosterone synthase as a novel strategy for breast cancer patients with elevated cardiovascular risks.
abstract: The application of aromatase inhibitors to postmenopausal breast cancer patients increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concentrations of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, that is, a given substituent showed an increase in inhibition of one enzyme, while it led to a decrease for the other enzyme. The compromise of this conflict led to compounds 3j, 3k, 3n, and 3p as potent and selective dual inhibitors of CYP19 and CYP11B2, especially compound 3p, which exhibited IC(50) values of 32 and 41 nM for CYP19 and CYP11B2, respectively, and a high selectivity toward CYP17 and CYP11B1. This compound is considered as a candidate for further evaluation in vivo.
authors.affiliation: Pharmaceutical and Medicinal Chemistry,  Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2-3, D-66123 Saarbrücken, Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Yin
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015363:Quinolones / Q000494:pharmacology*; D012307:Risk Factors; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D047072:Aromatase Inhibitors; D015363:Quinolones; D019405:Cytochrome P-450 CYP11B2