title: Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase.
abstract: Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration).
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70125 Bari, Italy. Electronic address: angela.stefanachi@uniba.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanachi
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), PO Box 15 11 50, D-66041 Saarbrücken, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hanke
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70125 Bari, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pisani
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70125 Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70125 Bari, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70125 Bari, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70125 Bari, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cellamare
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), PO Box 15 11 50, D-66041 Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70125 Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D000098:Acetophenones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000098:Acetophenones; D003374:Coumarins; D004791:Enzyme Inhibitors; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase
keywords: CYP11B1 inhibitors; CYP11B2; CYP17; CYP19; Coumarins; Imidazolyl-acetophenones