Browsing by Subject "Aminoquinolines"

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    8-aminoquinolines effective against Pneumocystis carinii in vitro and in vivo
    (American Society for Microbiology, 1999-10) Queener, Sherry F.; Bartlett, Marilyn S.; Nasr, Mohamed; Smith, James W.; Pharmacology and Toxicology, School of Medicine
    The activities of 25 8-aminoquinolines were compared in tests assessing the ability of the compounds to inhibit the growth of Pneumocystis carinii in culture. Six compounds were effective at or below 0.03 microM: CDRI 80/53, NSC19894, NSC305805, NSC305812, WR182234, and primaquine. Four others were effective at between 0.2 and 0.03 microM: NSC305835, WR225448, WR238605, and WR242511. Fourteen drugs were also tested in a standard model of P. carinii pneumonia in rats at daily doses of 2 mg/kg of body weight in drinking water. CDRI 80/53, NSC305805, NSC305835, and WR225448 were extremely effective in the animal model. The effectiveness of WR238605, WR242511, and primaquine in the rat model has been reported elsewhere (M. S. Bartlett, S. F. Queener, R. R. Tidwell, W. K. Milhouse, J. D. Berman, W. Y. Ellis, and J. W. Smith, Antimicrob. Agents Chemother. 35:277-282, 1991). The length of the alkyl chain separating the nitrogens in the substituent at position 8 of the quinoline ring was a strong determinant of anti-P. carinii activity.
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    Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization
    (PLOS, 2018-09-12) McAnally, Danielle; Siddiquee, Khandaker; Gomaa, Ahmed; Szabo, Andras; Vasile, Stefan; Maloney, Patrick R.; Divlianska, Daniela B.; Peddibhotla, Satyamaheshwar; Morfa, Camilo J.; Hershberger, Paul; Falter, Rebecca; Williamson, Robert; Terry, David B.; Farjo, Rafal; Pinkerton, Anthony B.; Qi, Xiaping; Quigley, Judith; Boulton, Michael E.; Grant, Maria B.; Smith, Layton H.; Ophthalmology, School of Medicine
    Neovascularization is the pathological driver of blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. The loss of vision resulting from these diseases significantly impacts the productivity and quality of life of patients, and represents a substantial burden on the health care system. Current standard of care includes biologics that target vascular endothelial growth factor (VEGF), a key mediator of neovascularization. While anti-VGEF therapies have been successful, up to 30% of patients are non-responsive. Therefore, there is a need for new therapeutic targets, and small molecule inhibitors of angiogenesis to complement existing treatments. Apelin and its receptor have recently been shown to play a key role in both developmental and pathological angiogenesis in the eye. Through a cell-based high-throughput screen, we identified 4-aminoquinoline antimalarial drugs as potent selective antagonists of APJ. The prototypical 4-aminoquinoline, amodiaquine was found to be a selective, non-competitive APJ antagonist that inhibited apelin signaling in a concentration-dependent manner. Additionally, amodiaquine suppressed both apelin-and VGEF-induced endothelial tube formation. Intravitreal amodaiquine significantly reduced choroidal neovascularization (CNV) lesion volume in the laser-induced CNV mouse model, and showed no signs of ocular toxicity at the highest doses tested. This work firmly establishes APJ as a novel, chemically tractable therapeutic target for the treatment of ocular neovascularization, and that amodiaquine is a potential candidate for repurposing and further toxicological, and pharmacokinetic evaluation in the clinic.