RESUMEN
Despite the extensive literature describing the role of the ATP-gated P2X(3) receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X(3) antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85.
Asunto(s)
Descubrimiento de Drogas/métodos , Antagonistas del Receptor Purinérgico P2 , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacología , Tiofenos/química , Tiofenos/metabolismo , Tiofenos/farmacología , Animales , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Unión Proteica/fisiología , Ratas , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X3 , Relación Estructura-ActividadRESUMEN
An analysis of the binding motifs of known HIV-1 non-nucleoside reverse transcriptase inhibitors has led to discovery of novel piperidine-linked aminopyrimidine derivatives with broad activity against wild-type as well as drug-resistant mutant viruses. Notably, the series retains potency against the K103N/Y181C and Y188L mutants, among others. Thus, the N-benzyl compound 5k has a particularly attractive profile. Synthesis and SAR are presented and discussed, as well as crystal structures relating to the binding motifs.
Asunto(s)
Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Mutación , Pirimidinas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Descubrimiento de Drogas , Farmacorresistencia Viral/genética , VIH-1/genética , Modelos Moleculares , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
Asunto(s)
Fármacos Anti-VIH/química , Benzamidas/química , Antagonistas de los Receptores CCR5 , Inhibidores de Fusión de VIH/química , Pirroles/química , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores de Fusión de VIH/síntesis química , Inhibidores de Fusión de VIH/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Pirroles/síntesis química , Pirroles/farmacocinética , Ratas , Receptores CCR5/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed.
Asunto(s)
Antagonistas de los Receptores CCR5 , Piperidinas/química , Piperidinas/farmacología , Receptores CCR5/metabolismo , Animales , Células CACO-2 , Perros , Haplorrinos , Humanos , Piperidinas/farmacocinética , Ratas , Compuestos de Espiro/química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5â³, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.
Asunto(s)
Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridonas/química , Piridonas/farmacología , Receptores Purinérgicos P2X7/metabolismo , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Halogenación , HumanosRESUMEN
Organic impurities in compound libraries are known to often cause false-positive signals in screening campaigns for new leads, but organic impurities do not fully account for all false-positive results. We discovered inorganic impurities in our screening library that can also cause positive signals for a variety of targets and/or readout systems, including biochemical and biosensor assays. We investigated in depth the example of zinc for a specific project and in retrospect in various HTS screens at Roche and propose a straightforward counter screen using the chelator TPEN to rule out inhibition caused by zinc.
RESUMEN
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class.The binding mode maintains the beta13 and beta14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture.