Submission Details
Molecule(s):
Cc1ccncc1NC(=O)N(CCCNS(N)(=O)=O)C1CCCCC1
Cc1ccncc1NC(=O)N(CCCCNS(N)(=O)=O)C1CCCCC1
CNS(=O)(=O)NCCCCN(C(=O)Nc1cnccc1C)C1CCCCC1
Design Rationale:
Protein model x967: Sidechains of M49 and M165 have rotated to create a more open pocket. Sidechain of N142 also flipped providing different H-bond opportunities. Fragment expansion: Ligands based on extension of pyridyl fragment of x107 into pocket between M49 and M165 using position of benzyl group of x72 as an initial guide. Fragments found by searching REAL database, various sets aligned in Pharmit using x967 receptor model and x107 and x72 ligands to define pharmacophore features. Top set screened through SeeSAR and SeeSAR models also checked with CSM-lig. Cyclohexane linked to x107 pyridyl moiety by ureido group makes an excellent core scaffold. Elaborations from the pyridyl ring, ureido nitrogens and cyclohexyl ring system examined.
Other Notes:
Submitted compounds are similar to my last set (CHA-KIN-cd2), with pico-nanomolar affinity prediction in SeeSAR and CSM-lig scores ranging from 10.1 to 11.3, but the switch from sulphonamide to aminosulphonamide with a longer linker substantially reduces the complexity of synthesis. The 4 carbon spacer works better than the three carbon spacer, especially with the methylaminosulphonamide (compound 3), but not by much. I think synthesis should be trivial from reaction of 2,2,2-trifluoroethyl N-(4-methylpyridin-3-yl)carbamate (Chemspace CSC000718010 / EN300-174938, BD00996717) with the relevant substituted amino-cyclohexane, but am not completely sure re the reactivity of the aminosulphonamide N-[3-(cyclohexylamino)propyl]aminosulfonamide (Chemspace CSC017485300 / BBV-47370184) is a purchasable building block from UORSY. A Representative SeeSAR model ouptut (compound3) has been uploaded with this submission