Submission Details

Design Rationale:

JAG-UCB-a3ef7265-20 ideas Cl to nitrile lowers logP with precedent for increased potency trans Methyl locks axial position and buries another CH3 Cl to cyclopropyl inspection of structure suggests space to bury a cyclopropyl well between Met 165 and His41 benzopyran to tetrahydroquinoline aiming to pick up interaction with GLN189 indicated as important by Demetri benzopyran to tetrahydroquinoline and extend to displace water in P3 pocket quaternary centre chiral lock with burying extra Me group quaternary centre chiral lock with attempt to displace local water cyclopropyl to oxetane to probe if unsaturated character important and potential better solubility cyclopropyl to isopropyl simple test of importance of unsaturated character and burying slightly more lipophilicity alternate benzopyran isomer to induce anomeric axial lock, possible H-bond to water and CH2 on lipophilic region acetonide analog anomeric lock, bury 2 Me groups but modulate logP spiro analogue, buries CH2CH2, looses 1 NH and locks conformation spiromorpholine analog, potential easier synthesis and lower logP reduced amide - test if C=O is necessary and increase HBA on triazole & modify torsion bias around amide amide to sulfonamide swap to modify torsion bias around amide reversed amide - standard medchem Cl to Me standard medchem