Glucose-6-phosphatase catalytic enzyme inhibitors: Synthesis and in vitro evaluation of novel 4,5,6,7-tetrahydrothieno[3,2-c]- and -[2,3-c]pyridines

The discovery of the first class of potent glucose-6-phosphatase catalytic site inhibitors, substituted 4,5,6,7-tetrahydrothieno[3,2-c]- and -[2,3-c]p yridines, is described. Optimisation of this series involved solution phase combinatorial synthesis and very potent compounds were prepared with IC50 values down to 140 nM. The structure-activity relationship (SAR) of these c ompounds indicates that: a tetrahydrothieno[3,2-c]pyridine core ring system and the isomeric [2,3-c] system are equipotent and much better than the co rresponding benzo analogue, 1,2,3,4-tetrahydro-isoquinoline. The 4-substitu ent of the tetrahydrothieno[3,2-c]pyridine ring has to be a phenyl group, o ptionally substituted with a lipophilic 4-substituent, such as trifluoromet hoxy or chloro. The 5-substituent of the tetrahydrothieno[3,2-c]pyridine ri ng has to be a substituted benzoyl; anisoyl and (E)-3-furan-3-ylacryloyl ar e the best of the investigated groups. Substitution in the benzoyl ortho po sition seems to be forbidden, whereas substitution in the meta position is tolerated only if a methoxy pm a substituent is present. These SAR findings were parallel to those obtained in the 3,5,6,7-tetrahydrothieno[2,3-c]pyri dine system. Enantioselectivity in enzyme recognition was observed and the activity resided in all cases only in one of the enantiomers. (C) 2000 Else vier Science Ltd. All rights reserved.