RESUMEN
GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.
RESUMEN
Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral in vivo tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug-drug interactions was managed by optimizing the series for subcutaneous injection.
RESUMEN
High-throughput screening and subsequent hit optimization identified 1-piperidinylbenzimidazoles, exemplified by compound 1, as TRPV4 inhibitors. Lead optimization identified potent TRPV4 blocker 19, which has good target activity and pharmacokinetic properties. Inhibitor 19 was then profiled in an in vivo rat model, demonstrating its ability to inhibit TRPV4-mediated pulmonary edema.
RESUMEN
This Letter discloses a series of 2-aminothiadiazole amides as selective EP(3) receptor antagonists. SAR optimization resulted in compounds with excellent functional activity in vitro. In addition, efforts to optimize DMPK properties in the rat are discussed. These efforts have resulted in the identification of potent, selective EP(3) receptor antagonists with excellent DMPK properties suitable for in vivo studies.
Asunto(s)
Amidas/química , Química Farmacéutica/métodos , Receptores de Prostaglandina E/antagonistas & inhibidores , Receptores de Prostaglandina E/química , Tiadiazoles/química , Administración Oral , Animales , Perros , Diseño de Fármacos , Humanos , Modelos Químicos , Estructura Molecular , Unión Proteica , Ratas , Ratas Sprague-Dawley , Subtipo EP3 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
Aminomethylpiperazines, reported previously as being kappa-opioid receptor agonists, were identified as lead compounds in the development of selective urotensin receptor antagonists. Optimized substitution of the piperazine moiety has provided high affinity urotensin receptor antagonists with greater than 100-fold selectivity over the kappa-opioid receptor. Select compounds were found to inhibit urotensin-induced vasoconstriction in isolated rat aortic rings consistent with the hypothesis that an urotensin antagonist may be useful for the treatment of hypertension.
Asunto(s)
Química Farmacéutica/métodos , Piperazinas/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Taurina/análogos & derivados , Urotensinas/antagonistas & inhibidores , Acamprosato , Animales , Aorta/metabolismo , Diseño de Fármacos , Humanos , Hipertensión/tratamiento farmacológico , Modelos Químicos , Piperazinas/química , Ratas , Relación Estructura-Actividad , Taurina/efectos de los fármacosRESUMEN
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
Asunto(s)
Química Farmacéutica/métodos , Urotensinas/antagonistas & inhibidores , Administración Oral , Animales , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Diaminas/química , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Ratas , Receptores Opioides kappa/química , Estereoisomerismo , Relación Estructura-Actividad , Urotensinas/químicaRESUMEN
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
Asunto(s)
Compuestos de Anilina/farmacología , Piperidonas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Administración Oral , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Animales , Disponibilidad Biológica , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Peso Molecular , Piperidonas/síntesis química , Piperidonas/química , Ratas , Bibliotecas de Moléculas Pequeñas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.
Asunto(s)
Antihipertensivos/síntesis química , Bencimidazoles/síntesis química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Oxadiazoles/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Aorta/efectos de los fármacos , Aorta/fisiología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Presión Sanguínea/efectos de los fármacos , Técnicas In Vitro , Modelos Moleculares , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Quinasas Asociadas a rhoRESUMEN
An enantioselective total synthesis of the naturally occurring anticancer agent (-)-laulimalide is described. The synthesis is characterized by extensive use of new reaction methodologies based on catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions and transformations of the derived enantioenriched beta-lactones. The synthesis also incorporates a unique allenylstannane glycal acetate alkylation and chemoselective ring-closing metathesis reaction.
Asunto(s)
Paclitaxel/análogos & derivados , Paclitaxel/síntesis química , Taxoides , Animales , Antineoplásicos/síntesis química , Macrólidos , Poríferos/química , EstereoisomerismoRESUMEN
[reaction: see text] Optically active 4-substituted 2-oxetanones provide conduits for preparing 2,3-dihydro-4H-pyrone heterocycles. Enantioenriched beta-lactones are prepared by asymmetric catalytic acyl halide-aldehyde cyclocondensation reactions. Hydrazone anion-mediated beta-lactone ring opening and ensuing cyclization-dehydroamination of the derived beta-ketohydrazone afford the desired dihydropyrones (68-81%). Optimized lactone ring-opening-cyclization reaction conditions render a variety of optically active 4-substituted-2-oxetanones as effective precursors to enantioenriched 2,3-dihydro-4H-pyrones.