RESUMEN
An efficient one-pot synthesis of 4-substituted 3-amino-2-cyanothiophenes is described. Treatment of 2-alkyl or aryl substituted acetonitrile sequentially with 2.1 equiv of LDA, 1.1 equiv of O-ethyl thioformate, and 1.2 equiv of 2-chloroacetonitrile afforded the thiophenes in moderate to good yields. The thiophene core can be readily incorporated into more elaborate pharmaceutically relevant structures as demonstrated by converting 3-amino-2-cyano-4-phenylthiophene (1g) to various functionalized thieno[3,2-d]pyrimidines in only two steps.
Asunto(s)
Formiatos/química , Nitrilos/síntesis química , Tiofenos/síntesis química , Estructura Molecular , Nitrilos/química , Tiofenos/químicaRESUMEN
A G-Protein-coupled receptor-targeted library of aryloxypropanolamines and aryloxybutanolamines was efficiently executed using a novel, polymer-supported acyclic acetal linker, producing compounds in good yields and purities.
Asunto(s)
Aminas/síntesis química , Diseño de Fármacos , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/síntesis química , Aminas/farmacología , Técnicas Químicas Combinatorias , Reactivos de Enlaces Cruzados , Humanos , Polímeros , Propanolaminas , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Benzylic and allylic organozinc and Grignard reagents have been added to resin-bound imines to provide alpha-branched secondary amines. Many functional groups, including electrophilic groups, were compatible with this methodology. Three modules--a resin-bound primary amine, an aromatic aldehyde, and the organometallic--were independently varied to produce a combinatorial library of alpha-branched secondary amines designed as beta-3 adrenergic receptor agonists.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntesis química , Aminas/química , Benceno/química , Iminas/química , Zinc/química , Agonistas Adrenérgicos beta/química , Técnicas Químicas Combinatorias , Estructura Molecular , Relación Estructura-ActividadRESUMEN
N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.
Asunto(s)
Antineoplásicos/síntesis química , Quinasas CDC2-CDC28/antagonistas & inhibidores , Oxazoles/síntesis química , Tiazoles/síntesis química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Quinasas CDC2-CDC28/metabolismo , Línea Celular Tumoral , Sistema Libre de Células , Cristalografía por Rayos X , Ciclina E/metabolismo , Quinasa 2 Dependiente de la Ciclina , Perros , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Trasplante de Neoplasias , Oxazoles/farmacocinética , Oxazoles/farmacología , Fosforilación , Ratas , Proteína de Retinoblastoma/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Trasplante HeterólogoRESUMEN
A new efficient strategy was developed for the construction of the imidazo[1,5-a]quinoxalin-4-one ring system. The new method involves condensation of o-nitroaniline with glyoxylate in methanol followed by treatment of the resulting alpha-(o-nitroanilino)-alpha-methoxy acetate with tosylmethyl isocyanide (TosMIC) reagent to give 1-(o-nitrophenyl)imidazole-5-carboxylate. Reductive cyclization of the nitro imidazole carboxylate afforded imidazo[1,5-a]quinoxalin-4-one in three steps and 60% overall yield. The new method was successfully applied to the synthesis of BMS-238497, a novel and potent Lck inhibitor.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Imidazoles/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Quinoxalinas/síntesis química , Compuestos de Anilina/química , Ciclización , Inhibidores Enzimáticos/farmacología , Glioxilatos/química , Imidazoles/química , Quinoxalinas/químicaRESUMEN
A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described.
Asunto(s)
IMP Deshidrogenasa/antagonistas & inhibidores , Triazinas/síntesis química , Triazinas/farmacología , Animales , División Celular/efectos de los fármacos , Células Cultivadas , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Triazinas/químicaRESUMEN
[structure: see text] A modified approach to the synthesis of 2-(N-aryl)-1,3-oxazoles, employing an optimized iminophosphorane/heterocumulene-mediated methodology, and its application to the synthesis of BMS-337197, a potent inhibitor of IMPDH, are described.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , IMP Deshidrogenasa/antagonistas & inhibidores , Oxazoles/síntesis química , Oxazoles/químicaRESUMEN
Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats.