Development of Predictive Models of Injury for the Lower Extremity, Lumbar, and Thoracic Spine after discharge from Physical Rehabilitation
Technical Report,22 Sep 2016,21 Sep 2017
The Geneva Foundation Tacoma United States
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Accomplishment Overview Progress on this project has been excellent we narrowed the candidate list to two compounds AN15380 and AN16458, Table 1, as planned at grant outset. At the end of grant-year1 we had identified 4 compounds which met the candidate selection criteria AN15380, AN15551, AN14609, and AN15884, Table 2. Based on toxicity findings and the short and efficient synthetic pathways of AN15380 and AN16458, these two compounds were selected as pre-development candidates Table 3. AN15380 was synthesized at the 50 g scale and the synthesis of AN16458 at the 50g scale was completed. Inhibition of the hERG channel by AN15380 and AN16458 was low or absent. Based on the findings of strong toxicity at low doses in the MTD studies with AN16458 work on this molecule was suspended. We selected AN15380 to be tested in animal models of PAH in the prevention and treatment modes. AN15380 reduced pulmonary hypertension PH. The Atlanta VA team has examined AN15380 in a pilot hypoxia-induced PH study in mice, in the prevention mode. AN15380 administered orally at 30 mgkg QD to mice reduced PH significantly by 78, p0.0054 and pulmonary vessel wall thickness by 48, p0.002. There was no change in pulmonary arterial pressure in control normoxic animals treated or not-treated with AN15380. However, some toxicity was noted in the rat and mouse studies treated with 30 mgkg. These toxicities were also noted at lower concentrations of AN-15380 0.3 and 3 mgkg in both prevention and reversal models of hypoxiaSugen induced PH. In addition, toxicity at the lower concentrations occurred with minimal impact on PH progression. In summary, while novel rho kinase inhibitors were developed that met the proposed pharmacokinetic profiles, issues with toxicity and efficacy preclude advancing these agents beyond preclinical studies for the treatment of PH.
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