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    • The overall very satisfactory potency profile of compounds a

    2022-05-27

    The overall very satisfactory potency profile of compounds 7a–l suggests that 1,3,4-thiadiazole-2-carboxamide moiety was a suitable periphery group to add to the 3-phenylpropanoic DL-Menthol australia core in order to improve affinity to FFA1. The agonist activity in this series appears to be particularly sensitive to the substitutions in the anilide moiety, thus attesting for the importance of the latter for building efficient interactions with the receptor. Clearly, substitution in position 4 of the phenyl ring is particularly detrimental for the activity (7b, 7g, 7e, 7k). Substituents in positions 2 and 3 seem to be well tolerated, with the most active compounds (7c) having fluorine in position 2. The high potency of the 3,4-difluorophenyl compound (7j) is somewhat surprising in light of the relatively low potency of the 4-fluorophenyl compound (7e). We next evaluated the selectivity profile of the most potent GPR40 agonists (6a, 6c, 7c and 7j) against other free fatty acid receptors (FFA3/GPR41, FFA2/GPR43 and FFA4/GPR120). FFA2 and FFA3 agonists have a preference in binding short-chain fatty acids while FFA1 and FFA4 have a higher affinity to medium- and long-chain fatty acids.19, 20 As it is seen from the activity data against this panel of GPCRs, the four lead compounds displayed high selectivity for FFA1 (Table 2). To gain a structural understanding of improved potency of 6a compared to 5, we have docked 6a and 5 in the FFA1 binding site. As visualized in A, both compounds have a similar orientation within the binding cavity forming hydrogen bonds with R1835.39, Y913.37, Y2406.51 and the backbone of L1384.57. While the more potent agonists (TAK-875, AMG 837 and LY2881835) substitute the 1,3,4-thiadizole with a more hydrophobic benzene ring, thiadiazole is still well accommodated within the binding site. This can be justified by its propensity to form π–π interactions with W174EL2 and possibly F873.33. The phenyl ring of 5 is at the interhelical space of helices 3 and 4, forming hydrophobic interactions with V843.30, F883.34 and F1424.61 (B). In contrast, the same phenyl ring of 6a positions deeper within the binding cavity forming π–π stacking interactions with F883.34 and F1424.61 (C). It appears that the addition of a second phenyl ring in 6a slightly pulls the molecule inside the helical bundle. This is due to involvement of the second phenyl ring in hydrophobic interactions with V843.30 and L1354.54 and the π–π stacking interaction with F883.34. The formation of the aromatic network with the receptor could explain the 10-fold increase in potency observed for 6a compared to 5. The portion of 7a–l bearing the carboxylic acid functionality is similar to the 3-[4-(benzyloxy)phenyl]propanoic acid core of TAK-875. To investigate the conformational similarities between 7c (one of the most potent compounds in the series) and the TAK-875 co-crystallized with the receptor, both were docked onto FFA1 (Fig. 5). Indeed, the hydrophobic benzene ring of the 3-phenylpropanoic acid portion of 7c appears beneficial for agonist activity as it matches the hydrophobic environment of the active site. The position of 7c inside the binding cavity closely resembles that of TAK-875. However, the differences in activity is likely attributable to the variation of the agonist aromatic tail. The 2-fluorobenzene tail of 7c points straight to the lipid side, whereas in TAK-875, the 2,6-dimethylphenyl moiety points toward the extracellular side of the lipids (the two methyl substituents control the dihedral angle of the biphenyl portion of TAK-875). As a result, TAK-875 forms additional favorable π–π stacking contacts with F1424.61. In contrast, the terminal ring of 7c connected via a rigid planar amide group extends straight and forms, similarly to 6a (vide supra), hydrophobic interactions with P803.26, V813.27 and V843.30. It appears that the terminal ring of 7c is particularly prone to steric effects. Indeed, even moderately bulky substituents (such as those present in 7b, 7d, 7f, 7i and 7k) tend to lower the agonist potency.