Structure-activity relationships and binding model of novel aromatase inhibitors

Nonsteroidal aromatase inhibitors: Recent advances

“…The work was aimed at studying the SAR of NSAIs, and led to the development of a model describing the relative binding modes of both steroidal and nonsteroidal AIs. 111,112 The representation of aromatase was limited to the heme group, and the simultaneous binding of two type II inhibitors, S-fadrozole and (19R)-10-thiiranylestr-4-ene-3, 17-dione (10-TED) was studied by modeling the molecules, and looking for a relative orientation consistent with a pharmacophoric hypothesis. Both inhibitors were known to coordinate the heme iron with the lone pair-carrying nitrogen atom of S-fadrozole and the sulfur atom of 10-TED, respectively, and these atoms were selected as anchoring points.…”

Comparative molecular field analysis of non-steroidal aromatase inhibitors related to fadrozole

“…The low potency and lack of selectivity of aminoglutethimide prompted the search of new, more potent and less toxic derivatives and, recently, fadrozole (2) was discovered after the optimization of a series of Nbenzylimidazoles [2]. Subsequent work on fadrozole analogues led to the rationalization of the SAR of this class of compounds and to a hypothesis of interaction of the inhibitors with the enzyme based on a comparison between fadrozole and a steroidal inhibitor (19R)-10-thiiranylestr-4-ene-3,17-dione (3) [3,4]. Furet et al observed that both molecules possess an iron-coordinating function (the unsubstituted imidazolic N atom of fadrozole and the thiiranylic S atom of 3) and they proposed that the essential cyano group of fadrozole could mimic the carbonyl function at position 17 of the steroid [4].…”

Synthesis and evaluation of 4-triazolylflavans as new aromatase inhibitors

“…For example, compound 1a appeared to be 15 times less potent than the corresponding 4-imidazolylflavan A while inhibitory potency of compound 2a was 10 times lower than that of derivative B. Such findings were previously demonstrated by Marchand et al, 14 Vinh et al 16 as well as by Lang et al 17 who compared, in a series of cyanophenyl derivatives, the activity of letrozole with that of the imidazolyl analogue.…”

“…In fact, Lang et al demonstrated that the replacement of the imidazole moiety by a triazole one led on the one hand to lower in vitro inhibition and on the other hand to higher in vivo activity. 17 The increased in vivo activity of triazoles compared with imidazoles has been shown to result from increased metabolic stability of the triazole derivatives. 18 Additionally, the triazole derived aromatase inhibitors generally exhibit greater selectivity with respect to other steroidogenic and nonsteroidogenic P450 enzymes.…”

“…18 Additionally, the triazole derived aromatase inhibitors generally exhibit greater selectivity with respect to other steroidogenic and nonsteroidogenic P450 enzymes. 17 Therefore, further experiments on the in vivo inhibitory potency and on the selectivity toward other steroidogenic P450 enzymes will be performed regarding the potency of our compound 2a.…”