Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

“…More recently, a new mechanism to enhance the bioactivities of DPP‐IV inhibitors has been discovered, consisting of establishing interactions with residue Lys554 . Figure and Supporting Information Figure show three different situations described in the literature that lead to increased DPP‐IV activity in this manner: (a) the introduction of a carboxylic acid (see Figure A), (b) the introduction of a methanesulfonyl group (see Figure B and Supporting Information A), and (c) the introduction of a substituent that ends in a carbamoyl group (see Figure C and Supporting Information B) . In the case of compound 8n , adding a carboxylic acid in the right location to make a salt bridge interaction with Lys554 results in a 213‐fold increase in bioactivity relative to compound 8f (which has a methyl instead of a carboxylic acid; see Figure A).…”

“…Interestingly, a comparison of compounds 22f‐trans , 13 , and 7 (which only differ in the substituent of the piperidin‐4‐aminium moiety; see Figure B and Supporting Information Figure H) shows how introducing a π–π interaction with Tyr666 contributes modestly to improving bioactivity (2.6‐fold when comparing compounds 13 and 7 ; see Supporting Information Figure H) in comparison to filling the S 1 pocket better using a methyl substituent added to the phenyl ring (43.5‐fold when comparing compounds 22f‐trans and 13 ; see Figure B and Supporting Information Figure H). This demonstrates that full occupation of the hydrophobic S 1 pocket plays a role in the determination of DPP‐IV activity . In fact all the crystallized ligands in the PDB occupy the S 1 pocket, with most of them showing very few changes in the size and shape of the ligand moiety in this place (see Supporting Information Table ).…”

“…Comparison of the distribution of electrostatic surfaces between pairs of compounds that differ in their interactions with residue Lys554 Notes : For each panel, the compound with the highest activity is shown in purple on the left and the compound with the lowest activity is shown in green on the right. Molecules are labeled with the same names that identify them in the corresponding paper . The negative and positive electrostatic surface differences are shown in garnet and blue respectively (where the default value, i.e., 2.0 was used as the threshold for the surface difference between each pair).…”

“…In the 2D representation of each ligand, the structural differences between the compared compounds are highlighted. The different panels are arranged in order of decreasing disparity and correspond to different situations: in panel A , a carboxylic acid replaces a methyl group; in panel B , a methanesulfonyl replaces a trifluoromethyl group; and in panel C , a (carbamoylmethyl)oxidanyl group replaces a chlorine group . The salt bridge between Lys554 and compound 8n in panel A is shown as a red dotted line, while the hydrogen bond with compound 35a in panel C is shown as a black dotted line.…”

Identification of Dipeptidyl Peptidase IV Inhibitors: Virtual Screening, Synthesis and Biological Evaluation

“…A group of 38 different compounds, which were collected from different references, were divided into a training set ( Figure 3) and test set ( Figure S1; 18,[23][24][25][26][27][28][29][30][31][32]. All the compounds were selected according to the following rules: (i) both training and test sets should cover the widest possible range of molecular bioactivities (IC 50 ); (ii) both the low-active and high-active compounds should be included; (iii) both training and test sets should cover diverse structures.…”