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Papers by Michael Malamas
J Med Chem, 2009
The identification of small molecule aminoimidazoles as potent and selective human beta-secretase... more The identification of small molecule aminoimidazoles as potent and selective human beta-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsin D, renin, and pepsin. Our design strategy was supported by molecular modeling studies based on the cocrystal structure of the HTS-hit 3 in the BACE1 active site. These strategies enabled us to integrate pyridine and pyrimidine groups on 3 extending deep into the S3 region of the BACE1 binding pocket and enhancing the ligand's potency. Compound (R)-37 displayed an IC50 value for BACE1 of 20 nM, cellular activity of 90 nM, and…
Bioorgan Med Chem, 2001
A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their bio... more A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human b 3-adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl sulfonamide on the left-hand side of the compounds resulted in a number of potent full agonists at the b 3 receptor. Modification of the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human b 3 agonists with low affinities for b 1-and b 2-ARs. N-Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the b 3 potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full b 3 agonist (EC 50 =0.004 mM, IA=1.0) with > 500-fold selectivity over b 1-and b 2-ARs.
Bioorg Medicinal Chem Letter, 2001
As part of our investigation into the development of potent and selective human beta3 agonists, a... more As part of our investigation into the development of potent and selective human beta3 agonists, a series of thiazolidinedione analogues was prepared and evaluated for their biological activity on the human beta3-adrenergic receptor. The oxadiazolidinedione derivative 17 was found to be the most potent and selective compound in this study, with an EC50 value of 0.02 microM at the beta3 receptor, 259-fold selectivity over the beta1 receptor, and 745-fold selectivity over the beta2 receptor.
J Med Chem, 2009
The identification of small molecule aminoimidazoles as potent and selective human beta-secretase... more The identification of small molecule aminoimidazoles as potent and selective human beta-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsin D, renin, and pepsin. Our design strategy was supported by molecular modeling studies based on the cocrystal structure of the HTS-hit 3 in the BACE1 active site. These strategies enabled us to integrate pyridine and pyrimidine groups on 3 extending deep into the S3 region of the BACE1 binding pocket and enhancing the ligand's potency. Compound (R)-37 displayed an IC50 value for BACE1 of 20 nM, cellular activity of 90 nM, and…
Bioorgan Med Chem, 2001
A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their bio... more A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human b 3-adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl sulfonamide on the left-hand side of the compounds resulted in a number of potent full agonists at the b 3 receptor. Modification of the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human b 3 agonists with low affinities for b 1-and b 2-ARs. N-Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the b 3 potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full b 3 agonist (EC 50 =0.004 mM, IA=1.0) with > 500-fold selectivity over b 1-and b 2-ARs.
Bioorg Medicinal Chem Letter, 2001
As part of our investigation into the development of potent and selective human beta3 agonists, a... more As part of our investigation into the development of potent and selective human beta3 agonists, a series of thiazolidinedione analogues was prepared and evaluated for their biological activity on the human beta3-adrenergic receptor. The oxadiazolidinedione derivative 17 was found to be the most potent and selective compound in this study, with an EC50 value of 0.02 microM at the beta3 receptor, 259-fold selectivity over the beta1 receptor, and 745-fold selectivity over the beta2 receptor.