CYP17 Inhibitors. Annulations of Additional Rings in Methylene Imidazole Substituted Biphenyls: Synthesis, Biological Evaluation and Molecular Modelling

Abstract

Twenty-one novel compounds originating from two classes of annulated biphenyls were synthesized as mimetics of the steroidal A- and C-rings and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of the hepatic CYP enzyme 3A4. Potent CYP17 inhibitors were found for each class, compound 9 (17 and 71% at 0.2 and 2 microM, respectively) and 21 (591 nM). Compound 21 showed only weak inhibition of CYP3A4 (32 and 64% at 2 and 10 microM, respectively). Both compounds, however, exhibited moderate to strong inhibition of the glucocorticoid-forming enzyme CYP11B1. The most interesting compounds were docked into our protein model. They bound into one of the modes which we have previously published. New interaction regions were identified.

Biophysical Screening of a Focused Library for the Discovery of CYP121 Inhibitors as Novel Antimycobacterials

“…Experimental details on modification of cYY and mycocyclosin synthesis and analytical data can be found in the Supporting Information (SI, section 4). The synthesis of library compounds has been described previously: class I, class II, class III, class IV, class V, and class VI …”

Discovery and Biophysical Evaluation of First Low Nanomolar Hits Targeting CYP125 of M. tuberculosis

“…For surface plasmon resonance (SPR) spectroscopy guided identification of CYP125 binders, we started with a hand‐picked selection of 132 compounds from our in‐house CYP inhibitor library focusing on structural diversity. The library contained compounds designed for inhibition of human steroidal P450 enzymes, especially CYP17, CYP11B1/2, and CYP19 . These inhibitors are privileged to interact with P450 enzymes because of their nitrogen‐containing heterocycles, which enable coordination to the iron(II) center of heme .…”

“…As the library compounds were originally designed for the inhibition of human steroidogenic enzymes, it was important to compare their activities toward human steroidogenic and hepatic enzymes as well as bacterial CYP enzymes (Table ). Most compounds from our library were active in the nanomolar range against their respective target . From our 14 heme binders, we selected five on the basis of their LE scores to be the most promising hits (i.e., compounds C24 , C60 , C127 , C128 , and C130 ) for further selectivity evaluation.…”

“…Compounds for testing [i.e., LP10 , econazole ( Eco ), and choleste‐3‐en‐4‐one ( CHN )] were purchased from commercial suppliers and were used without further purification. Procedures for the synthesis of library compounds were previously reported . Detailed information can be found in Section S6 of the Supporting Information.…”

Hits identified in library screening demonstrate selective CYP17A1 lyase inhibition

“…Although abiraterone acetate is successful in prolonging patients' lives, its steroidal structure in conjunction with the high daily dose could possibly result in unwanted activation of steroid hormone signaling via wild type or mutant steroid hormone receptor stimulation, although this has not yet been reported in clinical studies. Therefore contemporary research focus lies on non-steroidal inhibitors [4][5][6][7][8][9][10][11]. Furthermore abiraterone evidently blocks glucocorticoid biosynthesis by inhibition of both, hydroxylase and lyase, activities of CYP17A1 leading to a secondary mineralocorticoid excess that makes substitution with a synthetic glucocorticoid (e.g.…”