b-Annulated 1,4-dihydropyridines as Notch inhibitors.

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 EC50 ≈ 2.

A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis.

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.

Pradefovir: a prodrug that targets adefovir to the liver for the treatment of hepatitis B.

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.

Synthesis and characterization of a novel liver-targeted prodrug of cytosine-1-beta-D-arabinofuranoside monophosphate for the treatment of hepatocellular carcinoma.

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.

Adenosine kinase inhibitors. 5. Synthesis, enzyme inhibition, and analgesic activity of diaryl-erythro-furanosyltubercidin analogues.

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.

An efficient synthesis of pyrrolo[2,3-d]pyrimidines via inverse electron demand diels-alder reactions of 2-amino-4-cyanopyrroles with 1,3,5-triazines.

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.