ABSTRACT
A series of small molecules with a piperidinyl core were synthesized and tested for binding affinity (IC50) at human Neuropeptide Y Y2 receptor. Various amide related analogs (ureas, reversed amides, and sulfonamides) were evaluated. Several potent and selective NPY Y2 antagonists were identified.
Subject(s)
Amides/chemistry , Receptors, Neuropeptide Y/antagonists & inhibitors , Amides/chemical synthesis , Amides/metabolism , Animals , Drug Evaluation, Preclinical , Humans , Microsomes/metabolism , Protein Binding , Rats , Receptors, Neuropeptide Y/metabolism , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/metabolism , Urea/chemical synthesis , Urea/chemistry , Urea/metabolismABSTRACT
The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
Subject(s)
Azepines/pharmacology , Histamine H3 Antagonists/pharmacology , Pyridines/pharmacology , Amides/chemistry , Animals , Azepines/chemistry , Drug Evaluation, Preclinical , Pyridines/chemistry , RatsABSTRACT
Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
Subject(s)
Azepines/chemistry , Histamine H3 Antagonists/chemistry , Pyrrolidines/chemistry , Receptors, Histamine H3/chemistry , Administration, Oral , Animals , Azepines/chemical synthesis , Azepines/pharmacokinetics , Brain/metabolism , Dogs , Drug Evaluation, Preclinical , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Mice , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Rats , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of imidazole containing histamine H(3) receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.
Subject(s)
Blood-Brain Barrier/drug effects , Brain/drug effects , Chemistry, Pharmaceutical/methods , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/chemical synthesis , Imidazoles/chemistry , Animals , Brain/metabolism , Drug Design , Drug Evaluation, Preclinical , Guinea Pigs , Histamine H3 Antagonists/metabolism , Humans , Ligands , Models, Chemical , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H(3) receptor antagonist. Both histamine H(3) receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H(3) antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies(2) indicate the peripheral anionic site (PAS) of AChE interacts with the beta-amyloid (betaA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of betaA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H(3) receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.
Subject(s)
Cholinesterase Inhibitors/chemistry , Histamine H3 Antagonists/chemistry , Models, Molecular , Alzheimer Disease/drug therapy , Drug Evaluation, Preclinical/methods , Humans , Quantitative Structure-Activity RelationshipABSTRACT
Aplysamine-1 (1), a marine natural product, was synthesized and screened for in vitro activity at the human and rat histamine H3 receptors. Aplysamine-1 (1) was found to possess a high binding affinity for the human H3 receptor (Ki = 30+/-4 nM). Synthetic analogs of 1, including des-bromoaplysamine-1 (10) and dimethyl-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-ethyl}-amine (13), were potent H3 antagonists.