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491. DESIGN AND SYNTHESIS OF N-[4- 2, 4-DIAMINO-5-PROPYL-7HPYRROLO[2, 3-D]PYRIMIDIN-6-YLSULFANYL ; -BENZOYL]-L-GLUTAMIC ACID AS A POTENT INHIBITOR OF DIHYDROFOLATE REDUCTASE AND AS AN ANTITUMOR AGENT. Aleem Gangjee 1, Hiteshkumar Jain 1, Sherry F. Queener 2, and Roy L. Kisliuk 3. 1 ; Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15282, Fax: 412-396-5593, gangjee duq , 2 ; Department of Pharmacology and Toxicology, Indiana University, 3 ; Department of Chemistry, School of Medicine, Tufts University N-[4- 2, 4-diamino-5-methylpyrrolo[2, 3-d]pyrimidin-6-yl ; thio]benzoyl]-L-glutamic acid 1 ; was recently discovered by Gangjee et al. as a potent dual inhibitor of dihydrofolate reductase DHFR ; and thymidylate synthase TS ; with IC50 values in the 10 -7 M range. Compound 1 also demonstrated potent antitumor activity against the growth of several NCI human tumor cell lines in culture with IC50 values of 10 -8-10 -7 M or less. Similar results were obtained with the C5-ethyl homolog 2. Molecular modeling suggests that homologation of the C5-methyl to a propyl could further enhance the binding to the target enzyme s ; and hence the antitumor activity. Thus compound 3, the C5-propyl homolog of compounds 1 and 2 was designed and synthesized. The synthesis and biological activity of compound 3 will be presented and discussed.

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Table 1 pharmacologic agents for the treatment of inflammatory bowel disease drug comments sulfasalazine azulfidine ; use as first-line drug for treatment of acute or chronic crohn's disease or ulcerative colitis; 15 percent of patients experience complications 5-aminosalicylic acid 5-asa ; preparations topical use suppository for patients with proctitis; use enema for patients mesalamine rowasa ; with proctosigmoiditis; both forms may be given intermittently as maintenance therapy to prevent relapse oral use in patients with colitis who cannot tolerate sulfasalazine; use time- mesalamine asacol ; release mesalamine pentasa ; for treatment of ileitis or ileocolitis olsalazine dipentum ; corticosteroids topical suppository or enema oral use for treatment of active ulcerative colitis or crohn's disease; may be required to prevent relapse parenteral use for treatment of severe ulcerative colitis or crohn's disease antibiotics not helpful for treatment of ulcerative colitis unless fulminating disease is present; may use metronidazole flagyl ; , ciprofloxacin cipro ; or other broad-spectrum agents for treatment of active crohn's disease or fistulas immunosuppressive agents azathioprine imuran ; or use in patients with chronically active ulcerative colitis or crohn's 6-mercaptopurine 6-mp; disease and or fistulas; often reduces or eliminates steroid purinethol ; requirements methotrexate use in patients with chronically active ulcerative colitis or crohn's disease; there is less experience with this agent than with azathioprine or 6-mercaptopurine cyclosporine sandimmune ; intravenous may be helpful in patients with fulminating ulcerative colitis if no response has occurred with high-dose corticosteroid therapy oral may be helpful in maintaining remission, but complications are more significant with oral cyclosporine than with azathioprine or 6- mercaptopurine sulfasalazine in 1939, the combination of a sulfa compound and salicylate was developed as a treatment for rheumatoid arthritis or ulcerative colitis and galantamine.
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Patients with refractory HF are hospitalized frequently for clinical deterioration, and during such admissions, they commonly receive infusions of both positive inotropic agents dobutamine, dopamine, or milrinone ; and vasodilator drugs nitroglycerin or nitroprusside ; in an effort to improve cardiac performance, facilitate diuresis, and promote clinical stability. Some physicians have advocated the placement of pulmonary artery catheters in patients with refractory HF with the goal of obtaining hemodynamic measurements that might be used to guide the selection and titration of therapeutic agents 364 ; . However, the logic of this approach has been questioned because many useful drugs for HF produce benefits by mechanisms that cannot be evaluated by measuring their short-term hemodynamic effects 191; 365 ; . Regardless of whether invasive hemodynamic monitoring is used, once the clinical status of the patient has stabilized, every effort should be made to devise an oral regimen that can maintain symptomatic improvement and reduce the subsequent risk of deterioration. Assessment of the adequacy and tolerability of orally based strategies may necessitate observation in the hospital for at least 48 h after the infusions are discontinued 366.

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TRAINING GROUND. As of November, Amtrak's Acela Express, the nation's first high-speed train, began carrying travelers between Washington and Boston. Amtrak officials believe that the Acela, which can reach speeds of 150 miles per hour, will compete for passengers with airline shuttles. Able to travel from New York to Boston in three and a half hours, the train currently stops at New Haven; stops at Stamford and New London will be added. Eventually, Amtrak will offer 19 daily round-trips, weekdays, between New York and Washington, and 10 round-trips between New York and Boston. Revenue from the high-speed train is necessary to help Amtrak, which must operate without federal subsidies by the end of the 2002 fiscal year. A business-class Acela ticket from New Haven to New York costs $60, compared to a MetroNorth fare of $14. FIRE FLIGHTERS. Sikorsky Aircraft has sold two of its S-70 Firehawk helicopters to Los Angeles County. Each firefighting whirlybird contains a 1, 000-gallon water tank, extended landing gear, rescue hoists, and a customized interior for emergency medical service use. The Firehawk is designed with special modifications that allow it to refill its tank more easily than other firefighting helicopters, enabling it to deliver more gallons per hour, according to Sikorsky officials. The aircraft is able to fill its tank through a snorkel hose while hovering over a water source; it can also land next to a source and have the water pumped in through a connector on the tank. Los Angeles County officials have allocated $25 million to buy the Firehawks, said a Sikorsky spokesman. --Compiled and edited by Karen Miller and ketoconazole. .
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