Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase case

New synthesis of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazoles, nanomolar inhibitors of glycogen phosphorylase

“…Compounds 6a-c with aliphatic substituents proved weak inhibitors and were much less efficient than the corresponding "parent" amides I (shown in Chart 1; for R = CH 3 : K i 32 µM [39]; R = C(CH 3 ) 3 : IC 50 7.5 mM [41]; R = CH 2 OH: K i 18 [42] or 20 [49] µM), however, the trend in the strength of inhibition remained the same (t-butyl derivatives were the less efficient followed by the methyl and hydroxymethyl compounds in both series).…”

Synthesis of variously coupled conjugates of d-glucose, 1,3,4-oxadiazole, and 1,2,3-triazole for inhibition of glycogen phosphorylase

“…Based on the verified bioisosteric replacement of NHCO by 1,2,3-triazole 180 for the glycogen phosphorylase case by enzyme kinetic and X-ray crystallographic investigations 16 (cf. Chart 1a, 1-4), the present study aimed at double replacement of the NHCONHCO moieties in acyl urea derivatives (compounds in entry 1) by two five membered heterocycles.…”

“…Kinetic and crystallographic studies showed a very high resemblance both in strength and structural features of binding between amides 1 and 2 and 1,2,3-triazoles à 3 and 4, respectively. 16,17 Constitutional isomeric C-glucopyranosyl (Chart 1a, B) proved significantly better inhibitors than amides A with the same aglycon 5,9 (compare inhibitor constants for 1 and 11 as well as 2 and 12, respectively). Based on the successful bioisos-…”

Tethered derivatives of d-glucose and pentacyclic triterpenes for homo/heterobivalent inhibition of glycogen phosphorylase

“…Comparison of 19 with the hydroxymethyl-triazole 56 shows that the presence of the OA moiety makes the inhibition somewhat better. However, 56 binds to the catalytic site, 37 while 19 can be expected to occupy the allosteric site. 29 Thus, the comparable inhibitory activities may …”