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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH064570-13
Application #
8664424
Study Section
Special Emphasis Panel (ZMH1-ERB-M)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
13
Fiscal Year
2014
Total Cost
$362,376
Indirect Cost
$16,070
Name
University of Rochester
Department
Type
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Zhang, Gang; Guo, Dongwei; Dash, Prasanta K et al. (2016) The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. Nanomedicine 12:109-22
Dong, Weiguo; Embury, Christine M; Lu, Yaman et al. (2016) The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-β degradation. J Neuroinflammation 13:184
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Li, Weizhe; Tong, Hsin-I; Gorantla, Santhi et al. (2016) Neuropharmacologic Approaches to Restore the Brain's Microenvironment. J Neuroimmune Pharmacol 11:484-94
Singh, Dhirender; McMillan, JoEllyn; Hilaire, James et al. (2016) Development and characterization of a long-acting nanoformulated abacavir prodrug. Nanomedicine (Lond) 11:1913-27
Sajja, Balasrinivasa R; Bade, Aditya N; Zhou, Biyun et al. (2016) Generation and Disease Model Relevance of a Manganese Enhanced Magnetic Resonance Imaging-Based NOD/scid-IL-2Rγc(null) Mouse Brain Atlas. J Neuroimmune Pharmacol 11:133-41
Bade, Aditya N; Gorantla, Santhi; Dash, Prasanta K et al. (2016) Manganese-Enhanced Magnetic Resonance Imaging Reflects Brain Pathology During Progressive HIV-1 Infection of Humanized Mice. Mol Neurobiol 53:3286-97

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