Efforts toward oral bioavailability in factor VIIa inhibitors.

Efforts toward developing orally bioavailable factor VIIa inhibitors starting from parenteral lead compound 1 are described. SAR resulted in improved physicochemical properties, leading to enhanced oral absorption in rat.

Novel 5-azaindole factor VIIa inhibitors.

The discovery and development of 5-azaindole factor VIIa inhibitors will be described.

Discovery of novel hydroxy pyrazole based factor IXa inhibitor.

Synthesis and biological data of a novel selective and efficacious factor IXa inhibitor are described along with its crystal structure in factor VIIa.

Factor VIIa inhibitors: a prodrug strategy to improve oral bioavailability.

We have developed a series of potent and selective factor VIIa inhibitors based on the 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-biphenyl-3-yl]-succinic acid scaffold. These amidine-containing compounds have low oral bioavailability. Herein, we describe our efforts to improve the oral bioavailability of the parent amidine via a prodrug strategy where the amidine basicity and polarity were reduced with either an alkoxy-amidine or a carbamate prodrug.

Synthesis and biological evaluation of a fluorine-18 labeled estrogen receptor-alpha selective ligand: [18F] propyl pyrazole triol.

The two estrogen receptor subtypes, ERalpha and ERbeta, play important roles in breast cancer. To develop an ERalpha imaging agent, we synthesized fluoropropyl pyrazole triol (FPPT, 2), an analog of our ERalpha-selective ligand PPT. FPPT retains the high ERalpha binding selectivity of its parent PPT.

An efficient route for the preparation of a 21-fluoro progestin-16 alpha,17 alpha-dioxolane, a high-affinity ligand for PET imaging of the progesterone receptor.

Two different synthetic routes were explored for the synthesis of fluoro furanyl norprogesterone (FFNP) 1, a high-affinity ligand for the progesterone receptor (PgR) that is being developed as a PET imaging agent for PgR-positive breast cancer. Both approaches proceed through a key intermediate, triol 5. The first approach, starting from keto-ketal 2, employed a dioxenyl group as a synthon for installing a corticosteroid side chain in keto-alcohol 4.