Project 2 will use hypothesis-driven medicinal chemistry to optimize URMC-099 and its analogs (referred to as URMC-099C*) based on their ability to provide neuroprotection in the in vitro and in vivo models of HAND utilized by Projects 1 and 3. Through iterative cycles of optimization. Project 2 will identify a development compound for the treatment of HAND that can be advanced to an IND filing. We have previously discovered new chemical series of MLKS inhibitors by screening proprietary libraries and modified these scaffolds to provide compounds with good cellular penetration and activity in secondary assays for kinase inhibition. Subsequent compounds from this series were optimized to provide MLKS inhibitors with high levels of CNS exposure upon i.v. dosing. A prototypical advanced lead compound, URMC-099, has demonstrated efficacy during in vivo murine brain imaging experiments monitoring leukocyte trafficking, microglial activation, and preservation of synaptic architecture. We therefore propose four specific aims to complete the advancement of this chemical series to development compound status: (1) Optimize URMC-099c* to obtain potent MLKS antagonists that demonstrate appropriate CNS exposure upon oral dosing as well as efficacy in Project 1's animal models;progress promising compounds for evaluation in Project S's models of HAND;(2) Optimize the kinase inhibition profile of URMC-099c* to minimize the risk of undesirable off target activity;(S) Optimize selected lead compounds to profiles in preclinical assays acceptable for application to the NIH RAID Program for IND Supporting Studies;and (4) Devise formulations and preliminary process research synthetic methods to insure a smooth development course for the compounds, acceptance for NIH [RAID funding, and subsequent technology transfers.
HAND is likely to afflict over half the people living with HIV-1, but cART cannot permanently eradicate neurologic disease. Thus, the goal of this program is to continue work from the previous 2nd cycle on the development of an entirely new MLKS inhibitor to reverse neuroinflammation and restore synaptic function in people with HIV-1 and HAND.
|Kelso, Matthew L; Elliott, Bret R; Haverland, Nicole A et al. (2015) Granulocyte-macrophage colony stimulating factor exerts protective and immunomodulatory effects in cortical trauma. J Neuroimmunol 278:162-73|
|Gendelman, Howard E; Mosley, R Lee; Boska, Michael D et al. (2014) The promise of nanoneuromedicine. Nanomedicine (Lond) 9:171-6|
|Gendelman, Howard E; Gelbard, Harris A (2014) Adjunctive and long-acting nanoformulated antiretroviral therapies for HIV-associated neurocognitive disorders. Curr Opin HIV AIDS 9:585-90|
|Guo, Dongwei; Li, Tianyuzi; McMillan, JoEllyn et al. (2014) Small magnetite antiretroviral therapeutic nanoparticle probes for MRI of drug biodistribution. Nanomedicine (Lond) 9:1341-52|
|Singh, Dhirender; McMillan, JoEllyn M; Liu, Xin-Ming et al. (2014) Formulation design facilitates magnetic nanoparticle delivery to diseased cells and tissues. Nanomedicine (Lond) 9:469-85|
|Singh, Dhirender; McMillan, JoEllyn M; Kabanov, Alexander V et al. (2014) Bench-to-bedside translation of magnetic nanoparticles. Nanomedicine (Lond) 9:501-16|
|Edagwa, Benson J; Zhou, Tian; McMillan, JoEllyn M et al. (2014) Development of HIV reservoir targeted long acting nanoformulated antiretroviral therapies. Curr Med Chem 21:4186-98|
|Ivanisevic, Julijana; Epstein, Adrian A; Kurczy, Michael E et al. (2014) Brain region mapping using global metabolomics. Chem Biol 21:1575-84|
|Gendelman, Howard E; Balogh, Lajos P; Bawa, Raj et al. (2014) The 4th Annual Meeting of the American Society for Nanomedicine. J Neuroimmune Pharmacol 9 Suppl 1:S1-3|
|Polesskaya, Oksana; Wong, Christopher; Lebron, Luis et al. (2014) MLK3 regulates fMLP-stimulated neutrophil motility. Mol Immunol 58:214-22|
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