ABSTRACT
A series of acyloxyalkyl and amidooxyalkyl ketones appended to a carbobenzyloxy aspartic acid core have been prepared. The most potent of these new inhibitors was 4i with a K(i) of 0.5 microM. These two series provide an improved understanding of the binding requirements for the hydrophobic prime side of ICE.
Subject(s)
Caspase Inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Ketones/pharmacology , Humans , Models, Molecular , Monocytes/drug effectsABSTRACT
Succinic acid amides have been found to be effective P2-P3 scaffold replacements for peptidic ICE inhibitors. Heteroarylalkyl fragments occupying the P4 position provided access to compounds with nM affinities. Utilization of an acylal prodrug moiety was required to overcome biopharmaceutical issues which led to the identification of 17f, a potential clinical candidate.
Subject(s)
Amides/chemistry , Caspase Inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Succinic Acid/chemistry , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Half-Life , Magnetic Resonance Spectroscopy , Models, Molecular , Stereoisomerism , Structure-Activity RelationshipABSTRACT
It is believed that beta-amyloid aggregation is an important event in the development of Alzheimer's disease. In the course of our studies to identify beta-amyloid aggregation inhibitors, a series of N-phenyl anthranilic acid analogs were synthesized and studied for beta-amyloid inhibition activity. The synthesis, structure-activity relationship, and in vivo activity of these analogs are discussed.
Subject(s)
Amyloid/chemistry , Chemistry, Pharmaceutical/methods , Fenamates/chemistry , Alzheimer Disease , Animals , Disease Models, Animal , Drug Design , Enzyme Inhibitors/pharmacology , Fenamates/chemical synthesis , Humans , Mice , Microscopy, Atomic Force , Models, Chemical , Molecular Structure , Peptides/chemistry , Structure-Activity RelationshipABSTRACT
Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure-activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.
Subject(s)
Amides/chemical synthesis , Aza Compounds/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Neuroprotective Agents/chemical synthesis , Tacrolimus Binding Protein 1A/antagonists & inhibitors , Tacrolimus Binding Protein 1A/chemistry , Amides/chemistry , Aza Compounds/chemistry , Binding Sites , Heterocyclic Compounds, 4 or More Rings/chemistry , Hydrogen Bonding , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Ligands , Neuroprotective Agents/chemistry , Structure-Activity Relationship , Tacrolimus/chemistryABSTRACT
A series of sulfonamides (1) has been prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase 1. These compounds were designed to improve potency by rigidifying the enzyme bound molecule through an intramolecular hydrogen bond. An X-ray crystal structure of a representative member of this series bound to the active site of ICE, confirms the presence of the hydrogen bonding interaction.
