N-(Pyridin-3-yl)benzamides as selective inhibitors of human aldosterone synthase (CYP11B2)

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.…”

Sequential comparison of aldosterone synthase inhibition and mineralocorticoid blockade in patients with primary aldosteronism

“…Thus, this ASI, at doses of 0.5-1 mg twice daily, cannot replace mineralocorticoid receptor blockade or adrenal surgery in patients with primary aldosteronism. These results establish a precise methodology for the clinical development of this class of drugs, and the development of second-generation ASIs much more selective for CYP11B2 [20] than LCI699 remains promising. These potent and long-acting ASIs with very high selectivity indices for CYP11B2 are required for the testing of this approach at much higher doses in patients with primary aldosteronism and in other settings [20].…”

“…These results establish a precise methodology for the clinical development of this class of drugs, and the development of second-generation ASIs much more selective for CYP11B2 [20] than LCI699 remains promising. These potent and long-acting ASIs with very high selectivity indices for CYP11B2 are required for the testing of this approach at much higher doses in patients with primary aldosteronism and in other settings [20]. It may be necessary to compare these compounds with both steroid and dihydropyridinebased mineralocorticoid receptor antagonists [21].…”