The Things That Every Person Ought To Know Concerning natural product librariesBAY 11-7082

ger substituents. The X ray crystal structure with the PKB selective analogue 10 bound to PKBB was determined and showed a really similar binding mode to that of 217 . The tert butyl substituent occupied the lipophilic pocket formed by the P loop of PKB, with the 4 amino substituent interacting with Glu236 and the backbone carbonyl of Glu279 in natural product libraries the ribose pocket. As an alternative to substituent variation within the 4 amino 4 benzylpiperidine series, we also investigated compounds with varied chain length amongst the 4 aminopiperidine and 4 chlorophenyl groups . The ether 19 was as potent as 2 against PKB but had no selectivity against PKA, which we speculated was due to the far more flexible linker group. Although the amide 20 had decreased affinity for PKB, the isomericamide 21 retained activity for PKB and showed some selectivity over PKA.
A set of analogues with the amide 21 had been investigated making use of substituent patterns corresponding to those studied for the 4 amino 4 benzylpiperidines . Most compounds had been potent against PKB, but selectivity was normally decreased against PKA when compared with the 4 benzylpiperidines shown in Table 1. Variation natural product libraries with the position with the chlorine atom within the aromatic ring showed that BAY 11-7082 4 substitution as in 21 was optimal. Other 4 substituents showed a decrease in PKB inhibitory activity with increasing size, and the 4 tert butyl analogue 27 in particular was less active than the rest with the analogues in this set. This contrasted with the structure activity partnership seen for the 4 benzylpiperidines, and we ascribed these differences to the presence with the longer and relatively inflexible amide spacer which could result in larger 4 substituents being unable to interact as favorably with PKB.
As with the 4 Haematopoiesis benzylpiperidines, the 2,4 dichlorobenzyl amide 28 gave improved selectivity for PKB over PKA. Other less lipophilic 2,4 dihalobenzyl amides retained activity at PKB but with decreased selectivity. In some cases, increases in PKA activity for the benzyl amides had been seen relative to nonamide comparators. Even though constrained by the amide, the longer linker will allow the lipophilic substituent to attain a different range of conformations in comparison with the straightforward 4 benzylpiperidines , resulting within the recovery of productive contacts to the P loop of PKA. Methylation with the amide NH of 21 to provide compound 33, and the conformationally constrained tertiary amides BAY 11-7082 34 and 35, led to loss of potency againstPKB.
The crystal structure of 21 bound to PKBB showed the inhibitor bound in very similar fashion to 2 and 10, with the 4 amino group forming interactions with Glu236 and the backbone carbonyl of Glu279, when the 4 chlorophenyl ring was located within the P loop lipophilic pocket . As observed natural product libraries for 2 and 10, the inhibitors fundamental amino group formed a favorable close contact with the sulfur ofMet282 , an interactionwhich is lost in PKA. It really is feasible that the proximity with the electronrich sulfur residue compensates for loss of hydration with the protonated amine on binding. 17 A feasible further interaction was also observed to the amide spacer of 21 with close approach with the amide NH within the inhibitor and the side chain of Asp293.
The 10 fold drop in BAY 11-7082 activity for the N methyl amide 33 relative to 21 may reflect the disruption of this conformation in that complex. The effect of substituting the pyrrolo pyrimidine bicycle by 7 azaindole, oxopurine, and pyrazolo pyridine was investigated for essentially the most potent and selective piperidine moieties . The bicyclic heteroaromatic groups form hydrogen bonds to a part of the kinase domain, referred to as the hinge region, that links the distinct N and C terminal lobes. 7 Azaindole was the original hinge binding fragment from which this compound series was derived. 15,17 The carbonyl functionality of 8 oxopurine was expected to make further interactions with PKB, particularly the residue Thr213 at the entrance to the hydrophobic pocket with the kinase which differs amongst PKB and PKA.
For a similar cause, the pyrazolo pyridine bicycle was selected to provide an further polar atom within the ligand in this region. The azaindole 36, the direct analogue of 2, showed similar potency but no selectivity for PKB over PKA. The 4 amidopiperidine containing azaindole 38 was also unselective. Introduction natural product libraries with the 4 tert butyl substituent to provide 37 elevated the selectivity, mirroring the structure selectivity partnership seen with the pyrrolo pyrimidines 2 and 27, but only to ca. 20 fold. The 7 azaindoles had been thus associated with normally reduce selectivity for PKB over PKA than the pyrrolo pyrimidines. We believe this reduction in selectivity arises from the replacement of a nitrogen within the pyrrolo pyrimidines by a carbon within the azaindoles. This modifications the preferred BAY 11-7082 conformation and orientation with the piperidine ring relative to the bicycle and thus the vectors with the fundamental amine and lipophilic substituents. Mainly because selectivity in this series arises from efficiently exploit