The aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in π-π staking interaction with Trp227 (partial overlapping) and in a T-shape π-π staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide.

Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60–70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.

Nicotinic acetylcholine receptors containing α9 subunits (α9*-nAChRs) are potential druggable targets arousing great interest within the nicotinic receptor family with a special focus on a pain treatment alternative to opioids. Non-peptidic small molecules selectively acting as antagonists at this receptor subtype, especially without any effect on the closely related α7-nAChR, still remain an unattained goal, the achievement of which would provide invaluable tools to validate such an approach. Here, through relatively few directed modifications of the cationic head and the ethylene linker, we have converted the 2-triethylammonium ethyl ether of 4-stilbenol (MG624), a well-known antagonist for both α7 and α9* receptors, into a set of selective antagonists of human α9*-nAChR.Among these, the compound with cyclohexyldimetylammonium head (7) stands out for having no agonist or antagonist effect at α7-nAChR along with very low binding affinity at both α7 and α3β4 nicotinic receptor subtypes. Applied alone at high supra-micromolar concentrations, 7 and the other selective α9* antagonists behaved as partial agonists at α9*-nAChRs with a very short duration of the response, most likely due to very rapid block of the open channel, as revealed by the occurrence of rebound current once the application is stopped and the channel is disengaged. The small (nearly null in the case of 7) post-application residual activity of ACh control stimulation seems to be related to the slow recovery of the rebound current.

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Acidic 4‐hydroxy‐1,2,3‐triazole is a proven bioisostere of acidic functions that has recently been used to replace the acidic moieties of biologically active leads. Straightforward chemical strategies for the synthesis of the three possible N‐alkylated 4‐hydroxy‐1,2,3‐triazole regioisomers have been designed and reported herein, by identifying the optimal conditions under which the alkylation of ethyl 4‐benzyloxy‐1,2,3‐triazolecarboxylate (compound 19) can be regiodirected to the triazole N(b) position and thus produce the only isomer that cannot be obtained via the cycloaddition reaction. Furthermore, an innovative platform for parallel synthesis, called Arachno and which has been patented by the authors' group, has been used to speed up the process, and an NMR study has been carried out to better understand the reactivity of compound 19 towards the N(b) position. A library of benzyloxy protected 4‐hydroxy‐1,2,3‐triazoles has been prepared using the two strategies: regiodirection for the N(b) and N(c) isomers and cycloaddition for the N(a) isomers; the processes are described herein. The three N‐alkylated regioisomer series have been characterized spectroscopically (NMR and MS). The subsequent catalytic hydrogenation of the 4‐benzyloxy protective group on the N‐alkylated‐4‐benzyloxy‐5‐ethoxycarbonyl‐1,2,3‐triazoles provided the corresponding substituted 4‐hydroxy‐1,2,3‐triazoles.