RESUMO
The Notch signaling pathway is involved in cell proliferation and differentiation, and has been recognized as an active pathway in regenerating tissue and cancerous cells. Notch signaling inhibition is considered a viable approach to the treatment of a variety of conditions including colorectal cancer, pancreatic cancer, breast cancer and metastatic melanoma. The discovery that the b-annulated dihydropyridine FLI-06 (1) is an inhibitor of the Notch pathway with an EC50â¯≈â¯2.5⯵M prompted us to screen a library of related analogs. After structure activity studies were conducted, racemic compound 7 was identified with an EC50â¯=â¯0.36⯵M. Synthesis of individual enantiomers provided (+)-7 enantiomer with an EC50â¯=â¯0.13⯵M, or about 20-fold the potency of 1.
Assuntos
Antineoplásicos/farmacologia , Di-Hidropiridinas/farmacologia , Receptor Notch1/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Células HCT116 , Humanos , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , EstereoisomerismoRESUMO
Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the therapeutic index of adefovir, 1-aryl-1,3-propanyl prodrugs were synthesized with the rationale that this selectively liver-activated prodrug class would enhance liver levels of the active metabolite adefovir diphosphate (ADV-DP) and/or decrease kidney exposure. The lead prodrug (14, MB06866, pradefovir), identified from a variety of in vitro and in vivo assays, exhibited good oral bioavailability (F = 42%, mesylate salt, rat) and rate of prodrug conversion to ADV-DP. Tissue distribution studies in the rat using radiolabeled materials showed that cyclic 1-aryl-1,3-propanyl prodrugs enhance the delivery of adefovir and its metabolites to the liver, with pradefovir exhibiting a 12-fold improvement in the liver/kidney ratio over adefovir dipivoxil.
Assuntos
Adenina/análogos & derivados , Fígado/metabolismo , Organofosfonatos/síntese química , Compostos Organofosforados/síntese química , Adenina/administração & dosagem , Adenina/síntese química , Adenina/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cães , Hepatócitos/metabolismo , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacocinética , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/farmacocinética , Pró-Fármacos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Cytotoxic nucleosides have proven to be ineffective for the treatment of hepatocellular carcinoma (HCC) due, in part, to their inadequate conversion to their active nucleoside triphosphates (NTP) in the liver tumor and high conversion in other tissues. These characteristics lead to poor efficacy, high toxicity, and a drug class associated with an unacceptable therapeutic index. Cyclic 1-aryl-1,3-propanyl phosphate prodrugs selectively release the monophosphate of a nucleoside (NMP) into CYP3A4-expressing cells, such as hepatocytes, while leaving the prodrug intact in plasma and extrahepatic tissues. This prodrug strategy was applied to the monophosphate of the well-known cytotoxic nucleoside cytosine-1-beta-D-arabinofuranoside (cytarabine, araC). Compound 19S (MB07133), in mice, achieves good liver targeting compared to araC, generating >19-fold higher cytarabine triphosphate (araCTP) levels in the liver than levels of araC in the plasma and >12-fold higher araCTP levels in the liver than in the bone marrow, representing a >120-fold and >28-fold improvement, respectively, over araC administration.
Assuntos
Antineoplásicos/farmacologia , Arabinonucleotídeos/síntese química , Carcinoma Hepatocelular/tratamento farmacológico , Monofosfato de Citidina/análogos & derivados , Fígado/efeitos dos fármacos , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Arabinofuranosilcitosina Trifosfato/sangue , Arabinonucleotídeos/farmacocinética , Arabinonucleotídeos/farmacologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Cromatografia Líquida de Alta Pressão , Monofosfato de Citidina/síntese química , Monofosfato de Citidina/farmacocinética , Monofosfato de Citidina/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Ratos , Distribuição TecidualRESUMO
Adenosine is an endogenous neuromodulator that when produced in the central and the peripheral nervous systems has anticonvulsant, anti-inflammatory, and analgesic properties. However, efforts to use adenosine receptor agonists are plagued by dose-limiting cardiovascular side effects. As an alternative, we explored the use of adenosine kinase inhibitors (AKIs) as potential antiseizure agents and demonstrated an adenosine receptor mediated therapeutic effect in the absence of overt cardiovascular side effects. These activities were associated with elevation of extracellular adenosine concentrations due to inhibition of AK in a site and event specific manner. Several tubercidin based AKIs, including the ribo- and lyxo-furanosyltubercidin analogues as well as the newly discovered erythro-furanosyltubercidin analogues, designed to prevent 5'-O-phosphorylation and associated toxicities, were tested for their analgesic activity in the rat formalin paw model. Described herein are the synthesis, enzyme inhibition structure-activity relationships (SARs) of erythro-furanosyltubercidin analogues, and SARs of analgesic activity of various classes of AKIs. Also reported is the characterization of a lead AKI, 19d (GP3966), an orally bioavailable compound (F% = 60% in dog) which exhibits broad-spectrum analgesic activities (ED50 < or = 4 mg/kg, per os) that are reversible with an adenosine receptor antagonist (theophylline).
Assuntos
Adenosina Quinase/antagonistas & inibidores , Adenosina/análogos & derivados , Analgésicos/síntese química , Tubercidina/análogos & derivados , Tubercidina/síntese química , Adenosina/efeitos adversos , Adenosina/síntese química , Adenosina/farmacologia , Administração Oral , Analgésicos/efeitos adversos , Analgésicos/farmacologia , Animais , Área Sob a Curva , Disponibilidade Biológica , Callithrix , Cães , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Tubercidina/efeitos adversos , Tubercidina/farmacologiaRESUMO
AMP-activated protein kinase (AMPK) is a heterotrimeric kinase that regulates cellular energy metabolism by affecting energy-consuming pathways such as de novo lipid biosynthesis and glucose production as well as energy-producing pathways such as lipid oxidation and glucose uptake. Accordingly, compounds that activate AMPK represent potential drug candidates for the treatment of hyperlipidemia and type 2 diabetes. Screening of a proprietary library of AMP mimetics identified the phosphonic acid 2 that bears little structural resemblance to AMP but is capable of activating AMPK with high potency (EC50 = 6 nM vs AMP EC50 = 6 µM) and specificity. Phosphonate prodrugs of 2 inhibited de novo lipogenesis in cellular and animal models of hyperlipidemia.
RESUMO
The scope of the inverse electron demand Diels-Alder reaction of 2-amino-4-cyanopyrroles (3a-e) with 1,3,5-triazines (1, 2) is reported. This methodology is suitable for one-pot syntheses of highly substituted and highly functionalized pyrrolo[2,3-d]pyrimidines that are the central heterocyclic nucleus of various nucleoside natural products such as toyocamycin, sangivamycin, and tubercidin.