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.