RESUMEN
NOD2 (nucleotide-binding oligomerization domain-containing protein 2) is an internal pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates host immune responses. Dysfunction of NOD2 pathway has been associated with a number of autoinflammatory disorders. To date, direct inhibitors of NOD2 have not been described due to technical challenges of targeting the oligomeric protein complex. Receptor interacting protein kinase 2 (RIPK2) is an intracellular serine/threonine/tyrosine kinase, a key signaling partner, and an obligate kinase for NOD2. As such, RIPK2 represents an attractive target to probe the pathological roles of NOD2 pathway. To search for selective RIPK2 inhibitors, we employed virtual library screening (VLS) and structure based design that eventually led to a potent and selective RIPK2 inhibitor 8 with excellent oral bioavailability, which was used to evaluate the effects of inhibition of RIPK2 in various in vitro assays and ex vivo and in vivo pharmacodynamic models.
RESUMEN
Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lead optimization of the imidazopyrazines, exemplified by 3 (KAI407), and show that optimized compounds within the series with improved pharmacokinetic properties achieve causal prophylactic activity in vivo and may have the potential to target the dormant stages of P. vivax malaria.
RESUMEN
On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.
Asunto(s)
Antimaláricos/farmacología , Imidazoles/farmacología , Malaria Falciparum/tratamiento farmacológico , Piperazinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacocinética , Disponibilidad Biológica , Células CACO-2 , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacocinética , Malaria Falciparum/parasitología , Ratones , Ratones Endogámicos BALB C , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacocinética , Plasmodium falciparum/metabolismo , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Pharmacologic antagonism of cannabinoid 1 receptors (CB1 receptors) in the central nervous system (CNS) suppresses food intake, promotes weight loss, and improves the metabolic profile. Since the CB1 receptor is expressed both in the CNS and in peripheral tissues, therapeutic value may be gained with CB1 receptor inverse agonists acting on receptors in both domains. The present report examines the metabolic and CNS actions of a novel CB1 receptor inverse agonist, compound 64, a 1,5,6-trisubstituted pyrazolopyrimidinone. Compound 64 showed similar or superior binding affinity, in vitro potency, and pharmacokinetic profile compared to rimonabant. Both compounds improved the metabolic profile in diet-induced obese (DIO) rats and obese cynomolgus monkeys. Weight loss tended to be greater in compound 64-treated DIO rats compared to pair-fed counterparts, suggesting that compound 64 may have metabolic effects beyond those elicited by weight loss alone. In the CNS, reversal of agonist-induced hypothermia and hypolocomotion indicated that compound 64 possessed an antagonist activity in vivo. Dosed alone, compound 64 suppressed extinction of conditioned freezing (10 mg/kg) and rapid eye movement (REM) sleep (30 mg/kg), consistent with previous reports for rimonabant, although for REM sleep, compound 64 was greater than threefold less potent than for metabolic effects. Together, these data suggested that (1) impairment of extinction learning and REM sleep suppression are classic, centrally mediated responses to CB1 receptor inverse agonists, and (2) some separation may be achievable between central and peripheral effects with brain-penetrating CB1 receptor inverse agonists while maintaining metabolic efficacy. Furthermore, chronic treatment with compound 64 contributes to evidence that peripheral CB1 receptor blockade may yield beneficial outcomes that exceed those elicited by weight loss alone.
Asunto(s)
Obesidad/tratamiento farmacológico , Piperidinas/farmacología , Pirazoles/farmacología , Pirimidinonas/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Agonismo Inverso de Drogas , Extinción Psicológica/efectos de los fármacos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Obesidad/metabolismo , Piperidinas/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Pirimidinonas/administración & dosificación , Pirimidinonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Rimonabant , Sueño REM/efectos de los fármacos , Distribución TisularRESUMEN
Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.
Asunto(s)
Antimaláricos/síntesis química , Imidazoles/síntesis química , Piperazinas/síntesis química , Aminoácidos/síntesis química , Aminoácidos/química , Aminoácidos/farmacología , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Antimaláricos/química , Antimaláricos/farmacología , Derivados del Benceno/síntesis química , Derivados del Benceno/química , Derivados del Benceno/farmacología , Línea Celular , Resistencia a Medicamentos , Femenino , Humanos , Imidazoles/química , Imidazoles/farmacología , Concentración 50 Inhibidora , Malaria/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Piperazinas/química , Piperazinas/farmacología , Plasmodium berghei , Plasmodium falciparum/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
Peptidic, non-covalent inhibitors of lysosomal cysteine protease cathepsin S (1 and 2) were investigated due to low oral bioavailability, leading to an improved series of peptidomimetic inhibitors. Utilizing phenyl succinamides as the P2 residue increased the oral exposure of this lead series of compounds, while retaining selective inhibition of the cathepsin S isoform. Concurrent investigation of the P1 and P2 subsites resulted in the discovery of several potent and selective inhibitors of cathepsin S with good pharmacokinetic properties due to the elimination of saturated aliphatic P2 residues.
Asunto(s)
Amidas/síntesis química , Catepsinas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Diseño de Fármacos , Masculino , Estructura Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Ratas , Ratas Wistar , Relación Estructura-Actividad , SuccinatosRESUMEN
A systematic study of anilines led to the discovery of a metabolically robust fluoroindoline replacement for the alkoxy aniline toxicophore in 1. Investigations of the P1 pocket resulted in the discovery of a wide tolerance of functionality leading to the discovery of 11 as a potent and selective inhibitor of cathepsin S.
Asunto(s)
Amidas/farmacología , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Diseño de Fármacos , Amidas/síntesis química , Amidas/química , Aminación , Derivados del Benceno/síntesis química , Derivados del Benceno/química , Derivados del Benceno/farmacología , Sitios de Unión , Catepsina K , Catepsina L , Catepsinas/química , Catepsinas/metabolismo , Cisteína Endopeptidasas/química , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/química , Etanol/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
We report a novel series of noncovalent inhibitors of cathepsin S. The synthesis of the peptidomimetic scaffold is described and structure-activity relationships of P3, P1, and P1' subunits are discussed. Lead optimization to a non-peptidic scaffold has resulted in a new class of potent, highly selective, and orally bioavailable cathepsin S inhibitors.
Asunto(s)
Carbamatos/síntesis química , Carbamatos/farmacología , Catepsinas/antagonistas & inhibidores , Oligopéptidos/síntesis química , Inhibidores de Proteasas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Carbamatos/farmacocinética , Humanos , Masculino , Imitación Molecular , Oligopéptidos/farmacología , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported.