title: Novel pentamidine analogs in the treatment of experimental Pneumocystis carinii pneumonia.
abstract: We have recently demonstrated that substitution of imidazoline moieties for the amidine groups of pentamidine produces a molecule that is effective against rat Pneumocystis carinii pneumonia and that is apparently less toxic than pentamidine. For this reason, 10 novel imidazoline substituted compounds were evaluated for their effect against rat P. carinii pneumonia. While several of the new compounds were observed to have advantages over pentamidine in the treatment of disease in the rat model, only one compound stood out as a potential new clinical agent. Treatment for 2 weeks with intravenous (i.v.) doses of 1,3-di(4-imidazolino-2-methoxyphenoxy)propane (DIMP) at 1 mg/kg per day produced an anti-P. carinii pneumonia effect equivalent to i.v. doses of pentamidine at 10 mg/kg per day. Although pentamidine and one of the test drugs, 1,3-di(4-imidazolinophenoxy)propane, showed no activity against P. carinii pneumonia when administered per os, DIMP exhibited potent anti-P. carinii pneumonia activity when given by daily gavage doses of 40 and 25 mg/kg. DIMP retained significant activity when given every other day by a gavage dose of 25 mg/kg. No toxicity was observed with the drug at any of the dose levels or by either of the routes of administration. However, the low solubility of the drug prevented testing at higher i.v. doses. Our conclusion is that DIMP has the potential of providing a safer and more effective alternative to pentamidine for the treatment of P. carinii pneumonia.
authors.affiliation: Department of Pediatric Infectious Disease, School of Medicine, University of North Carolina, Chapel Hill 27599.
authors.forename: S K
authors.initials: SK
authors.lastname: Jones
authors.forename: J E
authors.initials: JE
authors.lastname: Hall
authors.forename: M A
authors.initials: MA
authors.lastname: Allen
authors.forename: S D
authors.initials: SD
authors.lastname: Morrison
authors.forename: K A
authors.initials: KA
authors.lastname: Ohemeng
authors.forename: V V
authors.initials: VV
authors.lastname: Reddy
authors.forename: J D
authors.initials: JD
authors.lastname: Geratz
authors.forename: R R
authors.initials: RR
authors.lastname: Tidwell
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; C065259:1,3-di-(4-imidazolino-2-methoxyphenoxy)propane; C063539:butamidine; C065258:1,3-di(4-imidazolinophenoxyl)propane; D010419:Pentamidine