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    • exemplifies three of the compounds investigated in

    2023-01-02

    exemplifies three of the compounds investigated in the selection for a candidate drug (CD). Our first criteria was an IC <100nM in both the cell and enzyme assays, and the chloropyrazole BLX-2481 () did not fulfil that. Although relatively potent, the bicyclic arylamide BLX-1873 (), showed relatively low solubility and metabolic stability and poor pharmacokinetic properties. The triazole BLX-2477 () which had a decent IC in the cell assay (56nM) was more extensively investigated. Although it is a strong inhibitor of several human cytochrome P450’s, particularly 2C9 and 2C19, this was not considered a showstopper. Although the high metabolic stability may indicate that it inhibits its own metabolism by being a substrate for the CYP’s, this was not investigated at this point. The solution dilution as such did not show any genotoxicity in the SOS/umu assay, but this does not say anything about any possible genotoxicity of its metabolites or degradation products. As BLX-2477, despite its high plasma protein binding, had favourable pharmacokinetic properties: a long iv mean residence time (MRT) of about 1.8h, and high exposure in the 10-day toxicology study (150mg/kg p.o.) that is, a up to 589μM, it was selected as a CD. As already discussed, compounds may inhibit 15-LOX-1 and its orthologues from other species to a different degree. It is of course important that a CD exhibits good activity in the species that will be used in advanced in vivo studies and the activity of some of our compounds on 15-LOX-1 orthologues were thus investigated. From it is evident that compound does not inhibit the rat or the dog enzymes to any large extent, but shows good activity toward the pig orthologue. Consequently, preclinical in vivo studies needs to be conducted using a mini-pig model. In their search for 15-LOX-1 inhibitors for use in anti-stroke therapy, Maloney and Holman used a mouse model, but they identified their HTS hits by simultaneously screening both 15-LOX-1 and the mouse ortholog. Obviously, the compounds described in our Letter would not have been considered interesting in their study. Nevertheless, the importance of using 15-LOX-1 in (one of) the primary screen(s) must be emphasized. In conclusion we have developed pyrazole-3-carboxanilides, triazole-4-carboxanilides and 2-(3-pyrazolyl)benzoxazoles that are good inhibitors of 15-LOX-1. BLX-2477, -(2-chloro-4-fluorophenyl) triazole-4-carboxamide () was selected as a clinical candidate, but regrettably, adverse non-target associated effects were found during the toxicological studies using mini-pigs, which forced us to terminate the program. Acknowledgement This work was financially supported by Biolipox AB. The compounds described in the Letter were kindly provided by Hans-Erik Claesson, CEO, Biolipid AB, [email protected].
    Introduction Mammalian lipoxygenases (LOXs) belong to a family of non-heme iron-containing dioxygenases, which catalyze the hydroperoxidation of polyunsaturated fatty acids such as arachidonic and linoleic acids to related hydroperoxides [1]. A heterogeneous family of LOXs was found as 5-LOX, 12-LOX and 15-LOX isoforms which oxidize different position of the key substrate, arachidonic acid [2]. The LOX isoforms have been shown to be involved in the physiopathology and progression of several diseases in human thus would be emerged as an attractive target for therapeutic intervention [3]. Among them, 15-LOX has been implicated in cardiovascular complications (such as atherosclerosis), progression of certain cancers and chronic obstructive pulmonary disease (COPD) [4], [5]. Moreover, oxidation of arachidonic and linoleic acids by 15-LOX resulted in metabolites which have been shown to be pro-inflammatory [6] and pro-thrombotic [7]. Accordingly, the finding of new 15-LOX inhibitors has been interesting field in medicinal chemistry and drug discovery. Thiourea and sulfonamide derivatives have continuously absorbed attention of the medicinal chemists in view of their intense range of biological activities [8], [9], [10]. Thiourea derivatives have been employed as anti-inflammatory and antimicrobial [11], antimalarial [12], antitumoral [13], pesticidal [14], and anticancer agents [15]. Also sulfonamides comprise a significant class of drugs with diverse biological properties such as antimicrobial [16], [17], anticancer [18], [19], anti-inflammatory [20], and antiviral activities as well as HIV protease inhibitors [21]. Previously, several sulfonamide-based compounds have been reported as 15-LOX inhibitors [22], [23], [24]. Considering the above mentioned findings about importance of thiourea derivatives especially as anti-inflammatory and lipoxygenase inhibitory compounds, we designed novel phenylthiourea derivatives containing sulfonamide moiety as 15-LOX inhibitors. Since there is a polar cavity in the active site of lipoxygenase enzyme, thus the hydrophilic sulfonamide group as a proton acceptor or donor was connected to the phenylthiourea scaffold to combine their beneficial effects.