RESUMEN
In connection with a program directed at potent and balanced dual NK1/NK3 receptor ligands, a focused exploration of an original class of peptidomimetic derivatives was performed. The rational design and molecular hybridization of a novel phenylalanine core series was achieved to maximize the in vitro affinity and antagonism at both human NK1 and NK3 receptors. This study led to the identification of a new potent dual NK1/NK3 antagonist with pK i values of 8.6 and 8.1, respectively.
RESUMEN
The tachykinin NK1 and NK3 receptors are a novel drug target for schizophrenia in order to treat not only the positive and cognitive symptoms, but also the associated co-morbid depression and sleep disturbances associated with the disease. A novel class of peptidomimetic derivatives based on a versatile phenylglycine central core was synthesized and tested in vitro as dual NK1/NK3 receptor antagonists. From this series emerged compounds with good NK1 receptor affinity, although only modest dual NK1/NK3 receptor affinity was observed with one of these analogs.
Asunto(s)
Antipsicóticos/síntesis química , Diseño de Fármacos , Antagonistas del Receptor de Neuroquinina-1/síntesis química , Receptores de Neuroquinina-1 , Receptores de Neuroquinina-3/antagonistas & inhibidores , Antipsicóticos/metabolismo , Antagonistas del Receptor de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-3/metabolismo , Relación Estructura-ActividadRESUMEN
A series of phosphonate analogues related to perindopril and ramipril were prepared and tested to estimate their ability to inhibit angiotensin converting enzyme. These new synthesized compounds were active ACE inhibitors with a promising activity.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Organofosfonatos/química , Perindopril/análogos & derivados , Perindopril/farmacología , Ramipril/análogos & derivados , Ramipril/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Sitios de Unión , Dominio Catalítico , Activación Enzimática/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/metabolismo , Perindopril/síntesis química , Perindopril/metabolismo , Unión Proteica , Ramipril/síntesis química , Ramipril/metabolismo , EstereoisomerismoRESUMEN
AIMS: We have developed biochemical and cell based assays to characterize small therapeutic molecules that inhibit the DNA damage checkpoint enzyme, Chk1 (Checkpoint kinase 1). MAIN METHODS: To prepare a screen of large chemical libraries, we purified the full-length and the catalytic domain versions of human Chk1. We characterized their properties and then selected full-length Chk1 as the variant most suitable for screening. We then identified and characterized structurally different Chk1 inhibitors in cell based-assays by measuring cytotoxicity and checkpoint bypass activity. KEY FINDINGS: We treated human cells with topoisomerase I inhibitors and demonstrated that at the time of Chk1 inhibitor addition, the cells have damaged DNA and activated Chk1. One Chk1 inhibitor, the indolocarbazole S27888, was active in the checkpoint bypass assay. SIGNIFICANCE: Knowing that the protein kinase inhibitory properties are different for each inhibitor, it seems that only a limited range of inhibitory activity is tolerated by cells. Chk1 has an essential role in determining how cancer cells respond to genotoxic treatments, therefore, inhibitors of this protein kinase are of great medical interest.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Carbazoles/farmacología , Neoplasias del Colon/tratamiento farmacológico , Proteínas Quinasas/metabolismo , Inhibidores de Topoisomerasa I/farmacología , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Neoplasias del Colon/enzimología , Neoplasias del Colon/genética , Daño del ADN , ADN de Neoplasias/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Proteínas Quinasas/genética , Spodoptera/citologíaRESUMEN
Though neurokinin(1) (NK(1)) receptors are implicated in depressed states and their treatment, selective antagonists have disappointed in clinical trials. Accordingly, we designed a novel ligand, S41744 (2-piperazin-1-yl-indan-2-carboxylic-acid-(3-chloro-5-fluoro-benzyl)-methyl-amide), which both blocks NK(1) receptors and interferes with serotonin (5-HT) reuptake. S41744 mimicked the selective antagonist aprepitant in binding human (h)NK(1) receptors and in antagonising Substance-P-mediated Extracellular-Regulated-Kinase phosphorylation (pK(B), 7.7). Further, it dose-dependently (0.63-40.0 mg/kg, i.p.) displaced ex vivo [(3)H]-[Sar(9),Met(O(2))(11)]-Substance P binding to gerbil striatum, attenuated formalin-induced hind-paw licking in gerbils, and antagonised locomotion induced by i.c.v. administration of the NK(1) agonist GR73632 to guinea pigs. Like paroxetine, S41744 recognised h5-HT transporters, reduced synaptosomal uptake of 5-HT (pK(B), 7.9), and dose-dependently (0.63-10.0 mg/kg) elevated dialysis levels of 5-HT in the hippocampus and frontal cortex of freely-moving guinea pigs. Further, S41744 increased extracellular levels of 5-HT in frontal cortex and hippocampus of rats to a greater extent than paroxetine, and its inhibitory influence upon serotonergic perikarya was blunted relative to its affinity for 5-HT transporters. S41744 more potently blocked stress-induced vocalizations in guinea pigs than aprepitant and paroxetine, and it was active in forced-swim and marble-burying procedures of putative antidepressant properties in mice. While aprepitant displayed anxiolytic actions in stress-induced foot-tapping and social interaction tests in gerbils, paroxetine was anxiogenic and S41744 "neutral", reflecting balanced NK(1) antagonism and suppression of 5-HT reuptake. Moreover, S41744 shared anxiolytic actions of aprepitant in the rat Vogel Conflict Test. In conclusion, S41744 is an innovative NK(1) antagonist/5-HT reuptake inhibitor justifying further evaluation for treatment of stress-related disorders.
Asunto(s)
Indanos/farmacología , Indanos/uso terapéutico , Morfolinas/farmacología , Morfolinas/uso terapéutico , Antagonistas del Receptor de Neuroquinina-1 , Paroxetina/farmacología , Paroxetina/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Antidepresivos/toxicidad , Aprepitant , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Gerbillinae , Cobayas , Humanos , Indanos/toxicidad , Masculino , Ratones , Morfolinas/toxicidad , Actividad Motora/efectos de los fármacos , Dimensión del Dolor , Paroxetina/toxicidad , Piperazinas/toxicidad , Embarazo , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores de Neuroquinina-1/metabolismo , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/toxicidad , Estrés Fisiológico/efectos de los fármacosRESUMEN
The 1,5-benzothiazepine-4-one scaffold was earlier shown to provide efficient protease inhibitors. In this contribution, we describe its use in the design of factor VIIa/tissue factor inhibitors. A series containing a scaffold non-substituted on its aryl part led to compound 20 with an IC(50) of 2.16 microM. Following molecular modelling studies of this compound, a second series was prepared, which necessitated the synthesis of protected 7- or 8-substituted 1,5-benzothiazepine-4-one derivatives.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Diseño de Fármacos , Factor VIIa/antagonistas & inhibidores , Tiazepinas/síntesis química , Tromboplastina/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos/métodos , Factor VIIa/metabolismo , Humanos , Tiazepinas/administración & dosificación , Tiazepinas/farmacología , Tromboplastina/metabolismoRESUMEN
A series of thieno[3,2-b]pyrroloazepinones derivatives related to Hymenialdisine were prepared and tested for CHK1 inhibitory activity. Nanomolar inhibitions were achieved when electron-withdrawing substituents were introduced at position 3 of the thiophene ring.
Asunto(s)
Antineoplásicos/síntesis química , Azepinas/síntesis química , Química Farmacéutica/métodos , Proteínas Quinasas/metabolismo , Pirroles/síntesis química , Antineoplásicos/farmacología , Azepinas/farmacología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Electrones , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Pirroles/farmacología , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
This study characterized the novel neurokinin (NK)(1) antagonist, vestipitant, under clinical evaluation for treatment of anxiety and depression. Vestipitant possessed high affinity for human NK(1) receptors (pK(i), 9.4), and potently blocked Substance P-mediated phosphorylation of Extracellular-Regulated-Kinase. In vivo, it occupied central NK(1) receptors in gerbils (Inhibitory Dose(50), 0.11 mg/kg). At similar doses, it abrogated nociception elicited by formalin in gerbils, and blocked foot-tapping and locomotion elicited by the NK(1) agonist, GR73632, in gerbils and guinea pigs, respectively. Further, vestipitant attenuated fear-induced foot-tapping in gerbils, separation-induced distress-vocalizations in guinea pigs, marble-burying behaviour in mice, and displayed anxiolytic actions in Vogel conflict and fear-induced ultrasonic vocalization procedures in rats. These actions were mimicked by CP99,994, L733,060 and GR205,171 which acted stereoselectively vs its less active isomer, GR226,206. In conclusion, vestipitant is a potent NK(1) receptor antagonist: its actions support the utility of NK(1) receptor blockade in the alleviation of anxiety and, possibly, depression.
Asunto(s)
Conducta Animal/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Antagonistas del Receptor de Neuroquinina-1 , Sustancia P/farmacología , Animales , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Miedo/efectos de los fármacos , Femenino , Fluorobencenos , Gerbillinae , Relaciones Interpersonales , Locomoción/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Piperidinas/farmacología , Unión Proteica/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Wistar , Sustancia P/metabolismo , Vocalización Animal/efectos de los fármacosRESUMEN
The increased risk of thrombotic events associated with disease states such as diabetes and hypertension has been correlated with elevated circulating levels of Plasminogen Activator Inhibitor type-1 (PAI-1). In the present study we evaluate the benzothiophene derivative S35225 in comparison with two recently described inhibitors of PAI-1 activity Tiplaxtinin and WAY140312 on a panel of PAI-1 activity assays in vitro and in vivo. In a direct chromogenic assay, S35225 has an IC50 value of 44+/-0.9 microM similar to that of Tiplaxtinin (34+/-7 microM) and of WAY140312 (39+/-1 microM). In a clot lysis assay however, S35225 has a significantly lower IC50 value than Tiplaxtinin and WAY140312 (0.6+/-0.3 versus 22+/-5 and 16+/-2 microM respectively). Using a tPA capture assay to quantify active PAI-1 in rat or human plasma, neither WAY140312, nor Tiplaxtinin attained 50% inhibition of PAI-1 activity at the highest concentration tested (1 mM); S35225 has an IC50 value of 194+/-30 microM against active rat PAI-1 and 260+/-41 microM against active human PAI-1. The ability of the compounds to inhibit endogenous active PAI-1 in the rat following intravenous administration was also tested using the tPA capture assay. Only S35225 reduced circulating active PAI-1 levels in vivo (maximum inhibition of 76+/-5% at 10 mg/kg and 53+/-5% at 3 mg/kg). In contrast to Tiplaxtinin and WAY140312, S35225 is a direct inhibitor of PAI-1 activity in vitro in rat and human plasmas where vitronectin is constitutively present as well as in vivo in the blood after an intravenous administration in the rat.
Asunto(s)
Compuestos de Bifenilo/farmacología , Inhibidor 1 de Activador Plasminogénico/química , Tiofenos/farmacología , Animales , Compuestos de Bifenilo/química , Relación Dosis-Respuesta a Droga , Humanos , Ácidos Indolacéticos/química , Infusiones Intravenosas , Concentración 50 Inhibidora , Modelos Químicos , Ratas , Proteínas Recombinantes/química , Riesgo , Tiofenos/química , Trombosis , Factores de Tiempo , Activador de Tejido Plasminógeno/química , Vitronectina/químicaRESUMEN
Little is known concerning coupling of cerebral GABA(B) receptors to G protein subtypes, and the influence of positive allosteric modulators (PAMs) has not been evaluated. These questions were addressed by an antibody-capture/scintillation proximity assay strategy. GABA concentration-dependently enhanced the magnitude of [(35)S]GTPgammaS binding to Galphao and, less markedly, Galphai(1/3) in cortex, whereas Gq and Gs/olf were unaffected. (R)-baclofen and SKF97581 likewise activated Galphao and Galphai(1/3), expressing their actions more potently than GABA. Similar findings were acquired in hippocampus and cerebellum, and the GABA(B) antagonist, CGP55845A, abolished agonist-induced activation of Galphao and Galphai(1/3) in all structures. The PAMs, GS39783, CGP7930 and CGP13501, inactive alone, enhanced efficacy and potency of agonist-induced [(35)S]GTPgammaS binding to Galphao in all regions, actions abolished by CGP55845A. In contrast, they did not modify efficacies at Galphai(1/3). Similarly, in human embryonic kidney cells expressing GABA(B(1a+2)) or GABA(B(1b+2)) receptors, allosteric modulators did not detectably enhance efficacy of GABA at Galphai(1/3), though they increased its potency. To summarise, GABA(B) receptors coupled both to Galphao and to Galphai, but not Gq and Gs/olf, in rat brain. PAMs more markedly enhanced efficacy of coupling to Go versus Gi(1/3). It will be of interest to confirm these observations employing complementary techniques and to evaluate their potential therapeutic significance.
Asunto(s)
Encéfalo/metabolismo , Subunidades alfa de la Proteína de Unión al GTP G12-G13/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Receptores de GABA-B/fisiología , Sitio Alostérico/fisiología , Animales , Baclofeno/farmacología , Encéfalo/efectos de los fármacos , Línea Celular Transformada , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Humanos , Fenoles/farmacología , Ácidos Fosfínicos/farmacología , Propanolaminas/farmacología , Unión Proteica/efectos de los fármacos , Ensayo de Unión Radioligante/métodos , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
A series of urea analogues related to SA6817 and a GSK phosphonic acid with reported ACE inhibitory activity were prepared and tested for dual ACE and ECE activities. Although excellent ACE and NEP inhibition was achieved, only modest ECE inhibition was observed with one analogue.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/farmacología , Técnicas Químicas Combinatorias , Metaloendopeptidasas/antagonistas & inhibidores , Metaloendopeptidasas/farmacología , Naftalenos/farmacología , Urea/análogos & derivados , Urea/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Enzimas Convertidoras de Endotelina , Humanos , Estructura Molecular , Naftalenos/síntesis química , Naftalenos/química , Estereoisomerismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/químicaRESUMEN
The synthesis and evaluation of inhibitors of activated protein C (aPC) are reported. This serine protease is partly responsible for the degradation of factor VIIIa, involved in the regulation of bleeding in hemophilia A. Benzamidine-containing derivatives were found to be potent aPC inhibitors, some of them showing selectivity against the procoagulant protease thrombin. Moreover, compound 1 significantly restored the generation of thrombin in hemophiliac plasma.
Asunto(s)
Benzamidinas/farmacología , Hemofilia A/tratamiento farmacológico , Hemorragia/prevención & control , Proteína C/antagonistas & inhibidores , Inhibidores de Serina Proteinasa/farmacología , Benzamidinas/química , Factor VIIIa/metabolismo , Humanos , Estructura Molecular , Peso Molecular , Inhibidores de Serina Proteinasa/química , Relación Estructura-Actividad , Trombina/antagonistas & inhibidores , Trombina/biosíntesisRESUMEN
OBJECTIVE: To study the effects of a matrix metalloproteinase (MMP) inhibitor (S-34219) on osteoarthritis (OA) cartilage cultures and in the meniscectomized guinea pig model of OA. METHODS: The inhibitory activity of S-34219 on MMPs and aggrecanase was studied by fluorimetry and immunoassay, respectively. The effects of S-34219 on proteoglycan and collagen degradation were studied in cultures of rabbit and human cartilage. Medial meniscectomy was performed on 29 Hartley male guinea pigs, and these animals were randomly allocated to 1 of 3 groups: a control meniscectomized group (MNXc) receiving the vehicle, or a meniscectomized group receiving either 10 mg/kg or 20 mg/kg S-34219, administered twice per day by oral gavage for 12 weeks from day 1 after surgery. An additional group comprised sham-operated animals. Tibial cartilage from the operated left knee was processed for histologic assessment of OA lesions. RESULTS: The 50% inhibitory concentration (IC(50)) of S-34219 on MMPs 1, 2, 3, 8, 9, and 13 was 55, 0.1, 0.5, 0.1, 0.03, and 0.2 nM, respectively; the IC(50) on aggrecanase 1 was 190 nM. In cultured rabbit cartilage, 100 nM S-34219 strongly inhibited MMP-dependent degradation of collagen and proteoglycans. A concentration 100 times higher was needed to inhibit aggrecanase-dependent degradation. In cultures of human OA cartilage, 100 nM S-34219 inhibited spontaneous type II collagen degradation by 66% and proteoglycan degradation by only 22%. For in vivo studies, treated groups were compared with the MNXc group and the results, expressed as the percentage variation versus MNXc, were as follows: in the 10 and 20 mg/kg groups, a significant decrease (P < 0.05) in global histologic score (-12% and -14%, respectively) was observed, and this was associated with a significant increase (P < 0.05) in cartilage thickness (+19% and +18%, respectively). Neither dose level changed the proteoglycan content. CONCLUSION: In both treated animal groups, S-34219 significantly prevented the loss of cartilage thickness, probably by inhibiting collagen breakdown that normally leads to the erosion of fibrillated superficial areas. The absence of a protective effect on glycosaminoglycan loss, both in vitro and in vivo, suggests that aggrecanases may have an important role in cartilage loss. This study reinforces the relevance of these models for testing chondroprotective drugs, and the potential role of dual inhibitors of collagenase and aggrecanase as disease-modifying drugs in the management of OA.
Asunto(s)
Cartílago Articular/enzimología , Cartílago Articular/patología , Articulación de la Rodilla , Inhibidores de la Metaloproteinasa de la Matriz , Osteoartritis/enzimología , Osteoartritis/patología , Inhibidores de Proteasas/farmacología , Piridinas/farmacología , Sulfonas/farmacología , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Modelos Animales de Enfermedad , Epífisis/patología , Cobayas , Humanos , Técnicas In Vitro , Articulación de la Rodilla/enzimología , Articulación de la Rodilla/patología , Masculino , Osteoartritis/metabolismo , Proteoglicanos/metabolismo , Conejos , Tibia/patologíaRESUMEN
OBJECTIVE: To assess the relevance of collagen type II C-telopeptide fragments (CTX-II) as markers of cartilage degradation during adjuvant-induced arthritis in rats. METHODS: Rats were injected with Freund's adjuvant on day 0 and treated orally for 21 days twice a day with vehicle or 10 or 20 mg/kg of a newly designed matrix metalloproteinase inhibitor (MMP-Inh). Urine samples were collected for 24 h between days 19 and 20 and the concentration of the cartilage-derived CTX-II was measured with a 2-site, sandwich-type ELISA. To assess arthritis, inflammatory scores were determined, and changes in paw volumes were measured by plethysmography. RESULTS: On day 21, the inflammation was generalized in rats injected with Freund's adjuvant. The urinary concentration of CTX-II was significantly higher in arthritic rats than in control non-injected rats. Oral treatment of arthritic rats with MMP-Inh dramatically decreased the concentration of CTX-II in urine, with values returning to those of controls. Treatment simultaneously reduced the clinical variables of the disease. CONCLUSION: These results demonstrate that fragments of type II collagen in urine can be used as a measure of cartilage degradation in arthritic rats as well as potent non-invasive markers of the efficacy of chondroprotective treatments.
Asunto(s)
Artritis Experimental/enzimología , Cartílago Articular/enzimología , Colágeno Tipo II/orina , Metaloproteinasas de la Matriz/metabolismo , Animales , Artritis Experimental/fisiopatología , Artritis Experimental/orina , Cartílago Articular/efectos de los fármacos , Colágeno/orina , Colágeno Tipo I , Inhibidores Enzimáticos/farmacología , Femenino , Adyuvante de Freund , Concentración 50 Inhibidora , Inhibidores de la Metaloproteinasa de la Matriz , Fragmentos de Péptidos/orina , Péptidos/orina , Conejos , Ratas , Ratas Endogámicas LewRESUMEN
The synthesis and activity of novel benzothiophene derivatives are described. In the t-Pa-induced fibrin clot lysis assay, several compounds inhibit the formation of the tPa-PAI-1 complex with submicromolar IC(50). This class of compounds potentially represents a new generation of antithrombotic-fibrinolytic agents.
Asunto(s)
Fibrinolíticos/síntesis química , Inhibidor 1 de Activador Plasminogénico/metabolismo , Tiofenos/farmacología , Activador de Tejido Plasminógeno/antagonistas & inhibidores , Coagulación Sanguínea/efectos de los fármacos , Pruebas de Coagulación Sanguínea , Fibrinolíticos/farmacología , Humanos , Concentración 50 Inhibidora , Unión Proteica/efectos de los fármacos , Relación Estructura-Actividad , Tiofenos/síntesis química , Activador de Tejido Plasminógeno/metabolismoRESUMEN
Any treatment that could positively modulate central neuropeptides levels would provide a promising therapeutic approach to the treatment of cognitive deficits associated with aging and/or neurodegenerative diseases. Therefore, based on the activity in rodents, S 17092 (2S,3aS,7aS)-1][(R,R)-2-phenylcyclopropyl]carbonyl]-2-[(thiazolidin-3-yl)carbonyl]octahydro-1H-indole) has been selected as a potent inhibitor of cerebral prolyl-endopeptidase (PEP). By retarding the degradation of neuroactive peptides, S 17092 was successfully used in a variety of memory tasks. These tasks explored short-term, long-term, reference and working memory in aged mice, as well as in rodents and monkeys with chemically induced amnesia or spontaneous memory deficits. S 17092 has also been safely administered to humans, and showed a clear peripheral expression of its mechanism of action through its inhibitory effect upon PEP activity in plasma. S 17092 exhibited central effects, as evidenced by EEG recording in healthy volunteers, and could improve a delayed verbal memory task. Collectively, the preclinical and clinical effects of S 17092 have suggested a promising role for this compound as an agent for the treatment of cognitive disorders associated with cerebral aging.