Tumortargeted Anticancer Prodrugs And Their Biochemical Basis

One of the challenges in anticancer prodrug design is the identification of cancer-associated biochemical processes that can be utilized to release anticancer drugs from prodrugs. The obvious advantage of this approach is its high selectivity. Ideally, the cancer-associated biochemical processes do not or barely occur in normal cells. Two cancer-related features that have been extensively used for anticancer prodrug design are hypoxia and metastasis. Anticancer prodrugs based on the biochemical...

Cascade Activation Through Intramolecular Cyclization to Form Cyclic Drugs

Pilocarpine (139) is used as a topical miotic for controlling elevated intraocular pressure associated with glaucoma. The drug presents significant delivery problems due to its low ocular bioavailability (1-3 or less) and its short duration of action. The poor bioavailability was partly attributed to its poor permeability across the corneal membrane due to its low lipophilicity. Because of the low bioavailability, a large ophthalmic dose is required to enable an effective amount of pilocarpine...

Breast Cancer Resistance Protein Bcrp

BCRP is a new member of the ABC transporter superfamily initially cloned from a doxorubicin-resistant breast cancer cell line (MCF-7 AdrVp) selected with a combination of adriamycin and verapamil.229 Two other groups also independently identified this transporter from human placenta230 and human colon carcinoma cells (S1-M1-80),231 and named the protein ABCP (ABC transporter in placenta) and MXR (mitoxantrone resistance-associated protein), respectively. Molecular characterization revealed that...

Phase Ii Enzyme Systems

Glucuronosyl Transferases The uridine 5'-diphosphate glucuronyltransferases (UGTs) are a family of enzymes found in the endoplasmic reticulum that catalyze the transfer of glucuronic acid to nucleophilic sites on drugs and xenobiotics.55'56 The enzymes have broad substrate specificity and will conjugate phenols, carboxylic acids, alcohols, amines, nitrogen-containing heterocycles, and other moieties. UGT enzymes often catalyze the conjugation of metabolites of the CYP enzymes, which...

Improving The Oral Activity Of Calcitonin And Insulin Through Chemical Modification

Calcitonin is a 32-amino acid peptide hormone that participates in calcium and phosphorus metabolism. In mammals, the major source of calcitonin is from the parafollicular or C cells in the thyroid gland. Calcitonin contains a single disulfide bond, which causes the amino terminus to assume the shape of a ring. It is used to treat Paget's disease of bone. It also may be used to prevent continuing bone loss in women with postmenopausal osteoporosis and to treat hypercalcemia (too much calcium in...

Patents on Prodrugs

In recent years, there have been several litigated cases focusing on prodrug patents. The issues are related to whether infringement occurs when a prodrug is metabolized into a patented compound in the body of a patient. The prodrug issue was discussed in a lawsuit of Hoechst-Roussel Pharmaceuticals, Inc. v. Lehman in 1997.4 Hoechst-Roussel owned a U.S. patent which contained claims covering 1-hydroxy-tacrine, a drug for treatment of Alzheimer's disease. Hoechst sued Warner-Lambert for patent...

Xanthine Derivatives

Mechanism of action of drugs for asthma therapy. Schering Plough), which targeted airway receptors and exhibited reduced systemic side effects. A series of short-acting agents following the same general structure (shown in Figure 16.3A) were developed, including terbutaline (AstraZeneca) and fenoterol (Boehringer Ingelheim). As the chemistry of these drugs came to be understood, they were modified to achieve several things, including local metabolism to an active agent, increased...

Prodrugs And Intellectual Property Rightstwo Court Cases

The primary purpose for developing prodrugs is, of course, not to circumvent intellectual property rights but to obviate certain disadvantages that may have precluded an active agent from being used in clinical applications. Therefore, if undesirable properties of a drug molecule cannot be overcome by conventional changes in the pharmaceutical formulation or route of administration, the method of choice is to use one of the prodrug approaches discussed above. The parent drug usually came first...