Publications (42) View all
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Article: Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation.
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ABSTRACT: On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2' binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2'. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Aβ(40) in the plasma, CSF, and cortex of rats in a dose-dependent manner.Journal of Medicinal Chemistry 09/2012; · 4.80 Impact Factor -
Article: The synthesis and structure-activity relationship of 4-benzimidazolyl-piperidinylcarbonyl-piperidine analogs as histamine H3 antagonists.
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ABSTRACT: A structure-activity relationship study of the lead piperazinylcarbonylpiperidine compound 3 resulted in the identification of 4-benzimidazolyl-piperidinylcarbonyl-piperidine 6h as a histamine-3 (H(3)) receptor antagonist. Additional optimization of 6h led to the identification of compounds 11i-k with K(i) <or= 0.5 nM and good in vivo activity.Bioorganic & medicinal chemistry letters 09/2010; 20(17):5004-8. · 2.65 Impact Factor -
Article: Piperazine sulfonamide BACE1 inhibitors: design, synthesis, and in vivo characterization.
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ABSTRACT: With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2' sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Abeta(40) in transgenic mice with a single subcutaneous dose.Bioorganic & medicinal chemistry letters 03/2010; 20(9):2837-42. · 2.65 Impact Factor -
Article: Discovery of cyclic acylguanidines as highly potent and selective beta-site amyloid cleaving enzyme (BACE) inhibitors: Part I--inhibitor design and validation.
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ABSTRACT: A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180 degrees in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.Journal of Medicinal Chemistry 02/2010; 53(3):951-65. · 4.80 Impact Factor -
Chapter: Identification of CYP Mechanism-Based Inhibitors
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ABSTRACT: Metabolic drug-drug interactions occur when a drug A alters the pharmacokinetics of a coadministered drug B by either inhibiting, activating, or inducing the activity of the enzyme(s) that metabolize drug B. Inhibitory drug-drug interactions could result in serious adverse effects, including fatalities in patients receiving multiple medications. Cytochrome P450 superfamily (CYPs) are the major oxidative enzymes that participate in the metabolism of commercially available drugs. In addition to direct inhibition (reversible), these enzymes could be subjected to metabolism- or mechanism-based inhibition. Metabolism-based inhibition results from a metabolic product of the drug that is a more potent reversible inhibitor, whereas mechanism-based inhibition results from a metabolic product that binds irreversibly to the enzyme, rendering it inactive. Potent CYP inhibitors, including metabolism- and mechanism-based inhibition, are usually excluded from further consideration for development. The potential of new chemical entities (NCEs) to inhibit human CYPs, including metabolism- and mechanism-based inhibition, is assessed during the discovery stage in major pharmaceutical companies using in vitro screens. Metabolism- and mechanism-based inhibition is differentiated from direct inhibition primarily by being time dependent and involves catalytic steps. Metabolism- and mechanism-based inhibitors are differentiated by extensive dialysis, which would result in the recovery of enzyme activity for metabolism-based inhibition but not for mechanism-based inhibition. This chapter discusses the importance of identifying metabolism- and mechanism-based inhibitors and provides detailed experimental procedures for their identification early in drug discovery. Key WordsCYP–cytochrome P450–mechanism-based inhibition–drug-drug interactions–mechanism-based inactivation–human CYP02/2008: pages 245-262;
