Novel Pyridyl Substituted 4,5-Dihydro-[1,2,4]triazolo[4,3-a]quinolines as Potent and Selective Aldosterone Synthase Inhibitors with Improved in Vitro Metabolic Stability

Abstract

CYP11B2 inhibition is a promising treatment for diseases caused by excessive aldosterone. To improve the metabolic stability in human liver miscrosomes of previously reported CYP11B2 inhibitors, modifications were performed via a combination of ligand- and structure-based drug design approaches, leading to pyridyl 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolones. Compound 26 not only exhibited a much longer half-life (t1/2 ≫ 120 min), but also sustained inhibitory potency (IC50 = 4.2 nM) and selectivity over CYP11B1 (SF = 422), CYP17, CYP19, and a panel of hepatic CYP enzymes.

Targeting Steroidogenic Cytochromes P450 (CYPs) with 6‐Substituted 1‐Imidazolylmethylxanthones

“…To further investigate the binding of this series of compounds to the enzyme and rationalize the observed structureactivity relationships, compounds 1a, 1f,a nd 1g were docked into the X-ray crystal structure of CYP11B2 (PDB ID:4 DVQ). [17] Similar to the orientation of the naturals ubstrate deoxycorticosterone and some other previously reported CYP11B2 inhibitors, [18][19][20] these compounds stretched to the b2sheet rather than leaning on the I-helix (Figure 2). Not surprisingly,t he imidazole sp 2 -hybridized nitrogena tom coordinatesw ith the heme iron in an early perpendicular fashion,a nchoring the whole molecule (Figure 2A), while the xanthone core is twisted from the imidazole moiety and thusp arallel to the b2sheet.…”

“…[17] Similar to the orientation of the naturals ubstrate deoxycorticosterone and some other previously reported CYP11B2 inhibitors, [18][19][20] these compounds stretched to the b2sheet rather than leaning on the I-helix (Figure 2). [17] Similar to the orientation of the naturals ubstrate deoxycorticosterone and some other previously reported CYP11B2 inhibitors, [18][19][20] these compounds stretched to the b2sheet rather than leaning on the I-helix (Figure 2).…”

Drifting of heme-coordinating group in imidazolylmethylxanthones leading to improved selective inhibition of CYP11B1

“…Unsurprisingly, both compounds perpendicularly coordinate to the heme iron with their sp 2 hybridized imidazole N and the xanthone core is positioned nearly parallel to the heme plane ( Figures 3A and 3B). This core also stretches away from the I-helix, points to the β-β′ loop and parallels to the β2 sheet ( Figure 3A), similar to some previously identified CYP11B inhibitors [21,22]. In CYP11B2 crystal, the xanthone core leans on the β2 sheet; while it swings to the β′-C loop in the CYP11B1 homology model due to the subsidence of Phe130 ( Figures 3C and 3D).…”

Enantioselective reduction of aryl and hetero aryl methyl ketones using plant cell suspension cultures of Vigna radiata

“…(88.0%) with good yield (74%). This compound was an important building block in number of biologically active molecules (Hu et al 2015). At the same time, reaction proceeded smoothly with the six-membered ring compound 10a (product e.e.…”