ABSTRACT
The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model.
Subject(s)
Benzylamines/chemistry , Benzylamines/pharmacology , Parathyroid Hormone/antagonists & inhibitors , Parathyroid Hormone/blood , Receptors, Calcium-Sensing/metabolism , Administration, Oral , Animals , Benzylamines/administration & dosage , Benzylamines/pharmacokinetics , Male , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The alpha7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of alpha7 nAChR. SEN12333 shows high affinity for the rat alpha7 receptor expressed in GH4C1 cells (K(i) = 260 nM) and acts as full agonist in functional Ca(2+) flux studies (EC(50) = 1.6 microM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC(50) = 12 microM). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at alpha3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the alpha7-selective antagonist methyllycaconitine, indicating that it is mediated by alpha7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel alpha7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of alpha7 agonists for treatment of neurodegenerative and cognitive disorders.
Subject(s)
Cognition Disorders/drug therapy , Morpholines/therapeutic use , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/therapeutic use , Nicotinic Agonists/therapeutic use , Pyridines/therapeutic use , Receptors, Nicotinic/metabolism , Animals , Behavior, Animal/drug effects , Calcium/metabolism , Cell Line , Cognition/drug effects , Cognition Disorders/metabolism , Humans , Male , Membrane Potentials/drug effects , Molecular Structure , Morpholines/chemistry , Morpholines/pharmacokinetics , Morpholines/pharmacology , Motor Activity/drug effects , Neurodegenerative Diseases/metabolism , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/pharmacology , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacokinetics , Nicotinic Agonists/pharmacology , Patch-Clamp Techniques , Protein Binding , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Radioligand Assay , Rats , Rats, Long-Evans , Rats, Wistar , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
BACKGROUND: Glioblastomas (GBM) are typically comprised of morphologically diverse cells. Despite current advances in therapy, including surgical resection followed by radiation and chemotherapy, the prognosis for patients with GBM remains poor. Unfortunately, most patients die within 2 years of diagnosis of their disease. Molecular abnormalities vary among individual patients and also within each tumor. Indeed, one of the distinguishing features of GBM is its marked genetic heterogeneity. Due to the brain location of the tumor, the potential target inhibition for anticancer therapy must exhibit a manageable neurotoxicity profile in the concentration range in which the compounds show anti-proliferative activity.Kinesin KIF11 inhibition by small molecules such as Monastrol or Ispinesib is currently under investigation in the field of malignant tumors. In the current study we have assessed the relevance of the anti-mitotic Kinesin-like protein KIF11 in human GBM cell-lines. RESULTS: In this study the target was validated using a set of well characterised and potentially specific small molecule inhibitors of KIF11: an ispinesib analog, Monastrol, a Merck compound and 3 simplified derivatives of the Merck compound. Following an in silico selection, those compounds predicted to bear a favorable BBB permeation profile were assessed for their phenotypic effect on cell lines derived both from primary (U87MG) as well as treated (DBTRG-05-MG) glioblastomas. For some compounds, these data could be compared to their effect on normal human astrocytes, as well as their neurotoxicity on primary rat cortical neurons. The ispinesib analogue 1 showed an anti-proliferative effect on GBM cell lines by blocking them in the G2/M phase in a concentration range which was shown to be harmless to primary rat cortical neurons. Furthermore, ispinesib analog increased caspase 3/7-induced apoptosis in U87MG cells. CONCLUSION: In the area of cell cycle inhibition, KIF11 is critical for proper spindle assembly and represents an attractive anticancer target. Our results suggest that KIF11 inhibitors, when able to permeate the blood-brain-barrier, could represent an interesting class of anticancer drugs with low neurotoxic effects in the treatment of brain tumors.
Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/therapy , Gene Expression Regulation, Neoplastic , Glioblastoma/genetics , Glioblastoma/therapy , Kinesins/antagonists & inhibitors , Kinesins/physiology , Animals , Antineoplastic Agents/pharmacology , Astrocytes/drug effects , Benzamides/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cerebral Cortex/drug effects , Gene Expression Profiling , Humans , Quinazolines/pharmacology , Rats , Spindle Apparatus/drug effectsABSTRACT
Sodium (Na) channels continue to represent an important target for the development of novel anticonvulsants. We have synthesized and evaluated a series of 2,4(5)-diarylimidazoles for inhibition of the human neuronal Na(V)1.2 Na channel isoform. Starting with the unsubstituted lead compound previously published 3, SAR studies were performed introducing substituents with different physico-chemical properties. Lipophilicity (log D(7.4)) and basicity (pK(a)) of the compounds were measured and submitted for QSPR investigations. Some of the active compounds described had IC(50) values that were considerably lower than our lead compound. In particular, the m-CF(3) disubstituted 22 was the most active compound, inhibiting hNa(V)1.2 currents within the nanomolar concentration range (IC(50)=200 nM). In comparison, lamotrigine and phenytoin, two clinically used anticonvulsant drugs known to inhibit Na channels, had IC(50)'s values that were greater than 100 microM.
Subject(s)
Imidazoles/pharmacology , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolism , Cell Line , Electrophysiology , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Inhibitory Concentration 50 , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/chemistry , Sodium Channels/chemistry , Structure-Activity RelationshipABSTRACT
Alpha 7 nicotinic acetylcholine receptor (alpha(7) nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer's disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer's disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the alpha(7) nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed.
Subject(s)
Morpholines/chemistry , Morpholines/pharmacology , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Nicotinic/metabolism , Alzheimer Disease/drug therapy , Animals , Binding, Competitive , Calcium/metabolism , Cell Line , Cognition/drug effects , Electrophysiology , Humans , Morpholines/pharmacokinetics , Nicotinic Agonists/pharmacokinetics , Pyridines/pharmacokinetics , Rats , Rats, Wistar , Schizophrenia/drug therapy , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
This literature study article will present the possibility of a correlation between the energy meridians of Traditional Chinese Medicine, which can be traced back to the recently described primo vessels (formerly known as Bong-Han ducts), their composition, and the ability of tumors to proliferate and metastasize. It is proposed that microvesicular bodies such as exosomes, known to be involved in cell-to-cell communication, immune response, and tumor proliferation, could be moving across the body via the primo vascular system. The ubiquity of the primo vascular system and its penetration through the blood-brain barrier could also explain the ability of some peripheral tumors (e.g., breast tumor) to metastasize in the brain.
Subject(s)
Exosomes/physiology , Lymphatic System/physiology , Neoplasm Metastasis/physiopathology , Cell Proliferation , Humans , MeridiansABSTRACT
Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5',4':5,6]pyrimido[1,2- a]benzimidazol-5(6 H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2- a]benzimidazol-5(6 H)-one ( 25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Arthritis/drug therapy , Benzimidazoles/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrimidinones/chemical synthesis , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Crystallography, X-Ray , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Female , Injections, Intradermal , Interleukin-2/metabolism , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Reproducibility of Results , Stereoisomerism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/metabolismABSTRACT
A small family of novel 2,4(5)-diarylimidazoles were prepared through a simple and efficient synthesis and evaluated as potential inhibitors of hNa(v)1.2 sodium channel currents. One member of this series (4) exhibited profound inhibition of Na(v)1.2 currents, emerging as a promising lead compound for further structure-activity relationship studies for the development of novel sodium channel blockers.
Subject(s)
Chemistry, Pharmaceutical/methods , Imidazoles/chemical synthesis , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/chemistry , Sodium Channel Blockers/chemical synthesis , Sodium Channels/chemistry , Drug Design , Humans , Imidazoles/pharmacology , Ion Channel Gating , Models, Chemical , Molecular Structure , NAV1.2 Voltage-Gated Sodium Channel , Protein Isoforms , Sodium/chemistry , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/pharmacology , Structure-Activity RelationshipABSTRACT
Alpha7 agonists were identified via GOLD (CCDC) docking in the putative agonist binding site of an alpha7 homology model and a series of aminoalkyl benzoimidazoles was synthesised to obtain potentially brain penetrant drugs. The array was prepared starting from the reaction of ortho-fluoronitrobenzenes with a selection of diamines, followed by reduction of the nitro group to obtain a series of monoalkylated phenylene diamines. N,N'-Carbonyldiimidazole (CDI) mediated acylation, followed by a parallel automated work-up procedure, afforded the monoacylated phenylenediamines which were cyclised under acidic conditions. Parallel work-up and purification afforded the array products in good yields and purities with a robust parallel methodology which will be useful for other libraries. Screening for alpha7 activity revealed compounds with agonist activity for the receptor.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Brain/drug effects , Alkylation , Amination , Animals , Benzimidazoles/chemistry , Brain/metabolism , Calcium/metabolism , Cell Line , Chemical Phenomena , Chemistry, Physical , Chickens , Models, Molecular , Molecular Structure , Rats , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A parallel synthesis of aryl azoles with neuroprotective activity is described. All compounds obtained were evaluated in an in vitro assay using a NMDA toxicity paradigm showing a neuroprotective activity between 15% and 40%. The potential biological target of the active compounds was investigated by extensive literature searches based around similar scaffolds with reported neuroprotective activity. The most interesting molecules active in the NMDA toxicity assay (3a and 2g) showed moderate but significant activity in the inhibition of the Site 2 Sodium Channel binding assay at 10 microM. To confirm our hypothesis compounds 3a, c, f and 2g were tested in the Veratridine assay which is one of the excitotoxicity assays of relevance to NaV channels. The compounds tested showed an activity between 40% and 70%. The identification of neuroprotective small molecules and the identification of NaV channels as the potential site of action were the most important goals of this work.
Subject(s)
Azoles/pharmacology , Neuroprotective Agents/chemical synthesis , Animals , Azoles/chemical synthesis , Humans , N-Methylaspartate/toxicity , Neuroprotective Agents/pharmacology , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/pharmacology , Sodium Channels/drug effectsABSTRACT
A set of deazaguanine derivatives 1-3 targeting human purine nucleoside phosphorylase (hPNP) have been designed and synthesized. The new compounds are characterized by the presence of a structurally simplified "azasugar" motif to be more easily accessible by chemical synthesis than previous inhibitors. In the enzymatic assays, some of the new derivatives proved to be able to inhibit hPNP at low nanomolar concentration, thereby showing the same inhibitory potency in vitro as immucillin-H (IMH). Molecular docking experiments revealed a binding mode to hPNP essentially identical to that of IMH. As a result, the lower in vivo activity exhibited by 1d, compared with that exhibited by IMH, might be ascribed to differences in the pharmacokinetic, rather than pharmacodynamic, profile between these compounds. Derivatives 1a, 1d, and 2c emerged as the most active compounds within this new set and may represent interesting leads in the search for novel hPNP inhibitors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Purine-Nucleoside Phosphorylase/antagonists & inhibitors , Pyrimidinones/chemical synthesis , Pyrroles/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Purine-Nucleoside Phosphorylase/chemistry , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Structure-Activity RelationshipABSTRACT
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.
Subject(s)
Aminopyridines/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Carbamates/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Pyrimidines/chemical synthesis , Administration, Oral , Aminopyridines/chemistry , Aminopyridines/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Biological Availability , Carbamates/chemistry , Carbamates/pharmacology , Crystallography, X-Ray , Humans , In Vitro Techniques , Jurkat Cells , Lymphocyte Activation , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
Two libraries of substituted benzimidazoles were designed using a 'scaffold-hopping' approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions. Key examples showed inhibitory activity against both targets.
Subject(s)
Benzimidazoles/pharmacology , Nuclear Proteins/antagonists & inhibitors , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Benzimidazoles/chemistry , Cell Cycle Proteins , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme-Linked Immunosorbent Assay , Humans , Models, Molecular , Molecular Docking Simulation , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Protein Binding/drug effects , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-mdm2/chemistry , Proto-Oncogene Proteins c-mdm2/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Protein p53/metabolismABSTRACT
α7 nicotinic acetylcholine receptor agonists are promising therapeutic candidates for the treatment of cognitive impairment. As a follow up of our internal medicinal chemistry program we investigated a novel series of α7 nAChR agonists. Starting from molecular docking studies on two series of molecules recently developed in our laboratories, an alternative scaffold was designed attempting to combine the optimal features of these previously identified urea and pyrazole compounds. Based on our previous SAR knowledge and on predicted drug-like properties, a small library was synthesized in parallel manner, affording compounds with excellent α7 nAChR activity, selectivity and preliminary ADME profile.
Subject(s)
Drug Design , Pyrazoles/pharmacology , Urea/pharmacology , alpha7 Nicotinic Acetylcholine Receptor/agonists , Animals , Cell Membrane Permeability/drug effects , Dogs , Dose-Response Relationship, Drug , Humans , Male , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemical synthesisABSTRACT
Alpha-7 nicotinic acetylcholine receptors (α7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, α7 nAChR agonists represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort, around our previously reported chemical series, permitted the discovery of a novel class of α7 nAChR agonists with improved selectivity, in particular against the α3 receptor subtype and better ADME profile. The exploration of this series led to the identification of 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (25, SEN15924, WAY-361789), a novel, full agonist of the α7 nAChR that was evaluated in vitro and in vivo. Compound 25 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models (novel object recognition and auditory sensory gating).
Subject(s)
Azepines/chemical synthesis , Nicotinic Agonists/chemical synthesis , Pyrazoles/chemical synthesis , Receptors, Nicotinic/metabolism , Administration, Oral , Animals , Azepines/pharmacokinetics , Azepines/pharmacology , Brain/metabolism , Calcium/metabolism , Catalytic Domain , Cell Line , Cell Membrane Permeability , Cognition/drug effects , Dogs , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Male , Membrane Potentials/drug effects , Models, Molecular , Nicotinic Agonists/pharmacokinetics , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/chemical synthesis , Nicotinic Antagonists/pharmacokinetics , Nicotinic Antagonists/pharmacology , Patch-Clamp Techniques , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Radioligand Assay , Rats , Rats, Long-Evans , Reflex, Startle/drug effects , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
α7 Nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound 1 (SEN15924, WAY-361789) led to the identification of 12 (SEN78702, WYE-308775) a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models.
Subject(s)
Brain/drug effects , Cognition/drug effects , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Nicotinic Agonists/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , Receptors, Nicotinic/chemistry , Animals , CHO Cells , Calcium/metabolism , Chemistry, Pharmaceutical , Cricetinae , ERG1 Potassium Channel , Humans , Models, Molecular , Nicotinic Agonists/chemical synthesis , Piperidines/chemical synthesis , Pyrazoles/chemical synthesis , Rats , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
RATIONALE: α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored. OBJECTIVES: We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914. METHODS: Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the α7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914. RESULTS: WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction. CONCLUSIONS: These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.
Subject(s)
Cognition Disorders/drug therapy , Pyridines/pharmacology , Risperidone/pharmacology , Schizophrenia/drug therapy , Urea/analogs & derivatives , Animals , Antipsychotic Agents/pharmacology , Avoidance Learning/drug effects , Cognition Disorders/etiology , Drug Evaluation, Preclinical , Drug Interactions , Drug Therapy, Combination , Male , Memory/drug effects , Mice , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Receptors, Nicotinic/drug effects , Receptors, Nicotinic/metabolism , Schizophrenia/physiopathology , Urea/pharmacology , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
Subject(s)
Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Nicotinic/metabolism , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/pharmacology , Administration, Oral , Animals , Humans , Inhibitory Concentration 50 , Male , Models, Molecular , Nicotinic Agonists/administration & dosage , Nicotinic Agonists/pharmacokinetics , Protein Conformation , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rats , Receptors, Nicotinic/chemistry , Structure-Activity Relationship , Substrate Specificity , Urea/administration & dosage , Urea/pharmacokinetics , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A simple and efficient approach to selectively obtain 2,4(5)-diarylimidazoles suppressing formation of 2-aroyl-4(5)-arylimidazoles is described. The yield of each of the two products strongly depends on the reaction conditions employed. This reaction provides a simple method to prepare small libraries of biologically active compounds by parallel synthesis.