ABSTRACT
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.
Subject(s)
Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Factor VIIa/antagonists & inhibitors , Thrombosis/drug therapy , Administration, Oral , Animals , Biological Availability , Rats , Structure-Activity Relationship , Thrombin/antagonists & inhibitorsABSTRACT
The discovery and development of 5-azaindole factor VIIa inhibitors will be described.
Subject(s)
Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Factor VIIa/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Aza Compounds/chemistry , Crystallography, X-Ray , Factor VIIa/chemistry , Factor VIIa/metabolism , Indoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Synthesis and biological data of a novel selective and efficacious factor IXa inhibitor are described along with its crystal structure in factor VIIa.
Subject(s)
Factor IXa/antagonists & inhibitors , Pyrazoles/pharmacology , Serine Proteinase Inhibitors/pharmacology , Factor IXa/chemistry , Humans , Models, MolecularABSTRACT
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.
Subject(s)
Amidines/chemistry , Carbamates/chemistry , Factor VIIa/antagonists & inhibitors , Prodrugs/pharmacokinetics , Administration, Oral , Amidines/pharmacology , Animals , Biological Availability , Carbamates/pharmacology , Male , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
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. We prepared [(18)F]FPPT ((18)F-2) in high specific activity, but estrogen target tissue uptake in female rats was minimal and was not displaceable by unlabeled estradiol, probably because of the lipophilicity and triphenolic nature of FPPT.
Subject(s)
Pyrazoles/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Animals , Estrogen Receptor alpha , Estrogen Receptor beta , Female , Fluorine Radioisotopes , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Radiopharmaceuticals/metabolism , Radiopharmaceuticals/pharmacokinetics , Rats , Receptors, Estrogen/metabolism , Tissue DistributionABSTRACT
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. The second approach, starting from propargylic acetate 12b, involved the application of a two-step method, a Pd(II)-catalyzed oxidative rearrangement followed by a base-catalyzed acetate rearrangement of the intermediate unsaturated acetate 13b, to generate the requisite corticosteroid side chain in keto-acetate 14b. This intermediate was further elaborated to the final product 1 via efficient dihydroxylation with potassium permangnate, furan acetalization with scandium triflate, and mesylation and fluorination reactions. The palladium-catalyzed route is considerably more efficient than the dioxene approach for the synthesis of key intermediate triol 5, and the scandium triflate-catalyzed acetalization, in particular, led to a considerable improvement in the overall yield of the endo furan acetal alcohol 16a. This route provides a major improvement in the overall yield of the final progestin target, FFNP 1.
