Heteroaryl-Substituted Naphthalenes and Structurally Modified Derivatives:  Selective Inhibitors of CYP11B2 for the Treatment of Congestive Heart Failure and Myocardial Fibrosis

Abstract

Recently we proposed inhibition of aldosterone synthase (CYP11B2) as a novel strategy for the treatment of congestive heart failure and myocardial fibrosis. In this study the synthesis and biological evaluation of heteroaryl-substituted naphthalenes and quinolines (1-31) is described. Key step for the preparation of the compounds was a Suzuki cross-coupling. Activity of the compounds was determined in vitro using human CYP11B2 and selectivity was evaluated toward the human steroidogenic enzymes CYP11B1, CYP19, and CYP17. A large number of highly active and selective inhibitors of CYP11B2 was identified. The most active inhibitor was the 6-cyano compound 8 (IC50 = 3 nM) showing a competitive type of inhibition (K(i) value = 1.9 nM). The 6-ethoxy derivative 5 was found to be the most selective CYP11B2 inhibitor (IC50 = 12 nM; K(i) value = 8 nM; CYP11B1 IC50 = 5419 nM; selectivity factor = 451), showing no inhibition of human CYP3A4 (50 nM) and CYP2D6 (20 nM). Docking and molecular dynamics studies using our homology modeled CYP11B2 structure with selected compounds were performed. Caco-2 cell experiments revealed a large number of medium and highly permeable compounds and metabolic studies with 2 using rat liver microsomes showed sufficient stability.

Regioselective Synthesis of 4,5‐Diaryl‐1‐methyl‐1H‐imidazoles Including Highly Cytotoxic Derivatives by Pd‐Catalyzed Direct C‐5 Arylation of 1‐Methyl‐1H‐imidazole with Aryl Bromides

“…As shown in Scheme 1 and Entries 1, 2, and 3 of Table 6, these reactions provided the required products, 6c, 6e, and 6d, in 91, 54, and 55 % yield, respectively. Remarkably, the cross-coupling reactions producing 6d and 6e, unlike the arylation of 3,4-dichloro-2(5H)-furanone [25] and 4(5)-bromo-1H-imidazole [16d] under very similar experimental conditions, were not accompanied by an undesirable side reaction of aryl/ aryl interchange between Pd-and phosphane-bound phenyl groups. Nevertheless, the arylation of 11c and 11b met with limited success, providing modest yields but requiring long reaction times (Table 6, Entries 2 and 3).…”

Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase

“…[26] Subsequent optimization resulted in several classes of nonsteroidal highly potent hCYP11B2 inhibitors, i.e. imidazolyl-and pyridylmethylenetetrahydronaphthalenes and -indanes, [27,28] heterocycle substituted naphthalenes, dihydronaphthalenes, [29][30][31][32] pyridinyl substituted aliphatic cycles, [33] dihydroquinolinones, [34] indolines, [35] tetrahydropyrroloquinolinone, [36,37] and phenylsulfinyl naphthalenol. [38] Recently, several compound classes derived from the anaesthetic R-etomidate or the CYP19 inhibitor Fadrozole (Chart 1) were described as inhibitors of hCYP11B2.…”

Hits identified in library screening demonstrate selective CYP17A1 lyase inhibition

“…Aiming at the discovery of non-steroidal, selective lyase inhibitors as potential clinical candidates, a screening system capable of identifying suitable compounds in an early stage of development is required. In the present work we describe a new assay procedure which allows quick and easy to perform determination of lyase inhibition and demonstrate its usefulness by investigating selected structurally diverse compounds of our in-house steroidogenic CYP enzyme inhibitor library [17][18][19][20]. H(N)]-pregnenolone (1 mCi/mL, 21.1 Ci/mmol) was obtained from PerkinElmer LAS (Rodgau, Germany).…”