The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta (Abeta) peptide, the primary constituent of neurofibrillary plaques, implicated in Alzheimer's disease, by cleavage of the amyloid precursor protein. A small molecule inhibitor of BACE-1, (diaminomethylene)-2,5-diphenyl-1H-pyrrole-1-acetamide (1, BACE-1 IC(50)=3.7 microM), was recently described, representing a new small molecule lead. Initial SAR investigation demonstrated the potential of accessing the nearby S(3) and S(1)(') substrate binding pockets of the BACE-1 enzyme by building substituents off one of the phenyl substituents and guanidinyl functional group. We report here the optimization of guanidinyl functional group substituents on 1, leading to potent submicromolar BACE-1 inhibitors.
Ligands. -To maintain or improve in vitro 5-HT 1A affinity of buspirone and to increase the stability to CYP3A4 metabolism, arylpiperazines such as (III) and (VI) are designed and synthesized. Structural modifications in three regions of the buspirone scaffold are undertaken maintaining the protonable arylpiperazine recognition element in all designs. For the close structural analogues (III) and (VI) of buspirone significant improvements in stability against CYP3A4 are achieved while maintaining 5-HT1A affinity. -(TANDON, M.; O'DONNELL, M.-M.; PORTE, A.; VENSEL, D.; YANG, D.; PALMA, R.; BERESFORD, A.; ASHWELL*, M. A.; Bioorg. Med.
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