RESUMEN
OBJECTIVES: Rapid rate-of-kill (RoK) is a key parameter in the target candidate profile 1 (TCP1) for the next-generation antimalarial drugs for uncomplicated malaria, termed Single Encounter Radical Cure and Prophylaxis (SERCaP). TCP1 aims to rapidly eliminate the initial parasite burden, ideally as fast as artesunate, but minimally as fast as chloroquine. Here we explore whether the relative RoK of the Medicine for Malaria Venture (MMV) Malaria Box compounds is linked to their mode of action (MoA) and identify scaffolds of medicinal chemistry interest. METHODS: We used a bioluminescence relative RoK (BRRoK) assay over 6 and 48 h, with exposure to equipotent IC50 concentrations, to compare the cytocidal effects of Malaria Box compounds with those of benchmark antimalarials. RESULTS: BRRoK assay data demonstrate the following relative RoKs, from fast to slow: inhibitors of PfATP4>parasite haemoglobin catabolism>dihydrofolate reductase-thymidylate synthase (DHFR-TS)>dihydroorotate dehydrogenase (DHODH)>bc1 complex. Core-scaffold clustering analyses revealed intrinsic rapid cytocidal action for diamino-glycerols and 2-(aminomethyl)phenol, but slow action for 2-phenylbenz-imidazoles, 8-hydroxyquinolines and triazolopyrimidines. CONCLUSIONS: This study provides proof of principle that a compound's RoK is related to its MoA and that the target's intrinsic RoK is also modified by factors affecting a drug's access to it. Our findings highlight that as we use medicinal chemistry to improve potency, we can also improve the RoK for some scaffolds. Our BRRoK assay provides the necessary throughput for drug discovery and a critical decision-making tool to support development campaigns. Finally, two scaffolds, diamino-glycerols and 2-phenylbenzimidazoles, exhibit fast cytocidal action, inviting medicinal chemistry improvements towards TCP1 candidates.
Asunto(s)
Antimaláricos , Desarrollo de Medicamentos , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/farmacología , Artesunato , CloroquinaRESUMEN
N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high-throughput screen (HTS) of a subset of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs.
RESUMEN
A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.
Asunto(s)
Catepsina C/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Humanos , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Proteínas Recombinantes/química , Espectrometría de Fluorescencia , Relación Estructura-Actividad , Especificidad por Sustrato , Difracción de Rayos XRESUMEN
A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.
Asunto(s)
Cicloheptanos/química , Cicloheptanos/farmacología , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/química , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Animales , Broncoconstricción/efectos de los fármacos , Cicloheptanos/farmacocinética , Modelos Animales de Enfermedad , Cobayas , Humanos , Estructura Molecular , Antagonistas Muscarínicos/farmacocinética , Receptores Muscarínicos/química , Receptores Muscarínicos/metabolismoRESUMEN
The optimization of a new series of muscarinic M(3) antagonists is described, leading to the identification of AZD9164 which was progressed into the clinic for evaluation of its potential as a treatment for COPD.
Asunto(s)
Antagonistas Muscarínicos/química , Piperidinas/química , Quinuclidinas/química , Receptor Muscarínico M3/agonistas , Proteínas Sanguíneas/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Antagonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Unión Proteica , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinuclidinas/farmacología , Quinuclidinas/uso terapéutico , Receptor Muscarínico M3/metabolismo , Relación Estructura-ActividadRESUMEN
We report the design of novel, potent cPLA(2)α inhibitors that possess an α-methyl-2-ketothiazole that acts as a serine-reactive moiety. We describe the optimization of the series for potency and metabolic stability towards ketone reduction. This was achieved by attenuating the reactivity of the ketone using a combination of electronic and steric effects.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Fosfolipasas A2 Grupo IV/antagonistas & inhibidores , Cetonas/química , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Estabilidad de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Células HL-60 , Humanos , Concentración 50 Inhibidora , Cetonas/síntesis química , Cetonas/farmacología , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxidación-Reducción , Ratas , Serina/química , Tiazoles/químicaRESUMEN
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.
Asunto(s)
Inhibidores Enzimáticos/química , Isoxazoles/química , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Piridinas/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estructura Terciaria de Proteína , Piridinas/farmacología , RatasRESUMEN
Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low concentrations and a defensive cytotoxin at higher concentrations. The high active site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a new specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents toward remote specificity pockets, which become accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active site conservation.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Secuencia de Aminoácidos , Aminopiridinas/química , Aminopiridinas/farmacología , Animales , Bovinos , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Expresión Génica , Humanos , Isoenzimas/antagonistas & inhibidores , Masculino , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Mutación , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Quinazolinas/química , Quinazolinas/farmacología , RatasRESUMEN
The high lipophilicity of a series of cytosolic phospholipase A(2) inhibitors has been reduced by the modification of a decyloxyphenyl chain designed to mimic the arachidonyl group of the natural substrate. These changes have resulted in an improvement in the whole cell potency of the inhibitors.
Asunto(s)
Ácido Araquidónico/metabolismo , Citosol/química , Inhibidores Enzimáticos/farmacología , Fosfolipasas A/antagonistas & inhibidores , Ácido Araquidónico/química , Inhibidores Enzimáticos/síntesis química , Células HL-60 , Humanos , Concentración 50 Inhibidora , Imitación Molecular , Fosfolipasas A/metabolismo , Fosfolipasas A2 , Relación Estructura-ActividadRESUMEN
This review covers the recent literature on inhibitors of nitric oxide synthase (NOS) between 2001 and June 2002. Some of the potential therapeutic uses of selective NOS inhibitors are highlighted in the introduction, while the main part of the review covers the patent literature of small molecule NOS inhibitors being investigated primarily by the pharmaceutical industry.
Asunto(s)
Inhibidores Enzimáticos/química , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Animales , Industria Farmacéutica , Inhibidores Enzimáticos/farmacología , Humanos , Patentes como AsuntoRESUMEN
Using knowledge of the substrate specificity of cPLA(2) (phospholipases A(2)), a novel series of inhibitors of this enzyme were designed based upon a three point model of inhibitor binding to the enzyme active site comprising a lipophilic anchor, an electrophilic serine "trap", and an acidic binding moiety. The resulting 1,3-diheteroatom-substituted propan-2-ones were evaluated as inhibitors of cPLA(2) in both aggregated bilayer and soluble substrate assays. Systematic variation of the lipophilic, electrophilic, and acidic groups revealed a well-defined structure-activity relationship against the enzyme. Optimization of each group led to compound 22 (AR-C70484XX), which contains a decyloxy lipophilic side chain, a 1,3-diaryloxypropan-2-one moiety as a unique serine trap, and a benzoic acid as the acidic binding group. AR-C70484XX was found to be among the most potent in vitro inhibitors of cPLA(2) described to date being more than 20-fold more active against the isolated enzyme (IC(50) = 0.03 microM) than the standard cPLA(2) inhibitor, arachidonyl trifluoromethyl ketone (AACOCF(3)), and also greater than 10-fold more active than AACOCF(3) against the cellular production of arachidonic acid by HL60 cells (IC(50) = 2.8 microM).