Project Summary: The Medicinal Chemistry and Pharmaceutics Core will be headed by Dr. Patrick Sinko, the Parke- Davis Professor of Pharmaceufics and Drug Delivery in the School of Pharmacy and Associate Vice President for Research at Rutgers University. Dr. Sinko is well known for his expertise in mechanismbased pharmacokinefics and biopharmaceutics; transport and metabolism of drugs and drug analogues of natural compounds, drug targeting, bioavailability, and the oral and brain delivery of pharmaceufical macromolecules and bioconjugate delivery vehicles. Working with Ned Heindel, the Howard S. Bunn Professor of Chemistry at Lehigh University, he will directly interact with investigators in the Research and Development Projects evaluating countermeasures to sulfur mustard. Dr. Ned Heindel's expertise is in medicinal chemistry and the synthesis of small molecular weight organic compounds. Dr. Heindel holds 11 patents on candidate pharmaceuticals, one of which was transferred to ICN Corporation (an antipsoriatic) and three of which are licensed to Baxter Corporation (antivirals). He currently serves as a contractor for Azevan Pharmaceuticals, a venture capital start-up, where he directs the medicinal-organic synthesis program which has generated a series of promising novel clinical candidates which selectively block the effects of arginine vasopressin. He has a 40 year history of academic R&D in support of commercial drug development. Both Drs. Sinko and Heindel have expertise in medicinal chemistry, drug formulations and pharmaceutical drug development. The Medicinal Chemistry group will be involved in synthesis of drug leads including structural analogs needed to identify active pharmacophores and to optimize countermeasures forfurther development. Also important will be scale-up synthesis of candidate lead compounds for animal studies. The Pharmaceufics group will be primarily focused on opfimizing delivery of countermeasures to target tissues while minimizing toxicity. Their strategy will be ADME/PK tesfing of compounds generated, if results are satisfactory in vitro, they will be tested in vivo. If compounds fail, they can be reformulated using advanced drug delivery systems available in Dr. Sinko's laboratory. This assumes that failure is a result of poor deliverability- which is often the case. If countermeasures are successful in vivo, then IND-enabling studies will be performed in collaboration with the Pharmacology and Drug Development Core.