From indole to pyrrole-based inhibitors of the large GTPase, dynamin and the in-cell inhibition of clathrin mediated endocytosis.

Four libraries of dynole 34-2 (1, (E)-2-cyano-3-(1-(3-(dimethylamino)propyl)-1H-indol-3-yl)-N-octylacrylamide) analogues were synthesised with a view to maintaining or improving dynamin inhibition and expanding the in vivo utility of dynole 34-2 - a widely used dynamin chemical probe. A total of 62 compounds were assessed for dyn I inhibition, 39 and 13 analogues were identified with dynI IC50 values of <10 and < 5 μM, respectively: equipotent to Dynole 34-2. Eight sub 5 μM potent analogues were screened for their ability to block in cell inhibition of clathrin mediated endocytosis (CME) with six analogues with IC50 values ≤ 20 μM. Moreover, five of these analogues displayed improved cLogPs and drug scores relative to dynole 34-2, with the most potent dynamin active analogue: (E)-3-(4-(3-chlorophenyl)-1-(3-(dimethylamino)propyl)-1H-pyrrol-3-yl)-2-cyano-N-octylacrylamide (94) Dyn I IC50 = 3.1 ± 0.9 μM; the most CME active analogue: (E)-2-cyano-3-(1-(3-(dimethylamino)propyl)-4-(3-hydroxyphenyl)-1H-pyrrol-3-yl)-N-octylacrylamide (97) with IC50CME = 4.3 μM. Analogue 97 displayed the best combination of dyn and CME inhibition with IC50 values of 3.3 ± 2.3 and 4.3 μM, respectively.