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Cysteine Protease Inhibitors for the Treatment of Neurodegenerative Diseases and Osteoporosis

posted on 01.12.2019 by Ammar Jastaniah
Our lab has previously synthesized peptidomimetic cysteine protease inhibitors that are efficacious in mice models of Alzheimer's Disease.9 However, because they possess the highly reactive oxirane warhead, they exhibited high off-target effect as well as poor selectivity, as evidenced by their inhibition of the promiscuous cysteine protease, papain. Hence, in addressing such issues, we shifted our focus to the synthesis of reversible inhibitors, namely those that contain nitrile and α-ketoamide warheads. For both types of reversible peptidomimetics, literature compounds that are selective for calpain-1 and cathepsin B were utilized and modified. For the synthesis of the calpain-1 series, they required up to 12 reaction steps, most of which were optimized, including the final oxidation and purification step. In contrast, the synthesis of the peptidomimetic cathepsin B nitrile series was straightforward, although the procedures, too, were optimized. For our main accomplishment, it was the successful synthesis of novel, selective calpain-1, AbbVie derived α-ketoamides. Additionally, we synthesized the cathepsin B compounds; however, none of them displayed any noticeable activity, which could be attributed to discrepancies in the enzymatic screening assay protocols. For some of the calpain-1 compounds, they showed positive outcomes in in vitro cell assays and, therefore, were subsequently advanced for testing in animal models of neuronal degeneration such as oxidative stress. In chapter 2, another peptidomimetic inhibitor nitrile series was designed to target cathepsin K, also a cysteine protease. Cathepsin K plays a critical role in bone remodeling, particularly during bone resorption. For ailments such as osteoporosis, there is a substantial increase in cathepsin K activity, which, when inhibited, can be one way to treat the illness.10 Our approach was to synthesize small molecule inhibitors, which hybridized the scaffold structures of two nitrile compounds: the highly potent cathepsin K odanacatib and one of our previously synthesized inactive compounds. We observed that unlike the α-ketoamide series, chirality is not crucial for activity concerning the enantiomer pair of the new hybrid compounds, which were as equally potent for cathepsin K. Examples of the modifications to the lead scaffold included adding methylene to the rigid aromatic rings, changing the chiral center, or adding fluorine. Moreover, the nitrile warhead was replaced with the irreversible Michael Acceptor. SAR analysis for this series of compounds revealed that potency and selectivity for cathepsin K rely on the presence of the P2 leucine. Lastly, in chapter 3, we describe a complementary approach of AD pathology by focusing on the much-pursued amyloid hypothesis. It is established that lipidation of the apoE4 lipoprotein is compromised, which results in the inefficient clearance of amyloid plaques.11 Lipidation levels can be restored by increasing the expression levels of ABCA1 transporters. Our objective, therefore, is to synthesize small-molecule ABCA1 activators. One of the high throughput screening (HTS) hits for ABCA1 had an α-ketoamide functional group, and this scaffold was chosen for further optimization. All novel compounds demonstrated different ABCA1 fold activation levels, ranging from 1.29 to 2.20.



Thatcher, Gregory


Thatcher, Gregory


Medicinal Chemistry and Pharmacognosy

Degree Grantor

University of Illinois at Chicago

Degree Level


Degree name

PhD, Doctor of Philosophy

Committee Member

Gaisina, Irina Moore, Terry Bruzik, Karl Driver, Thomas

Submitted date

December 2019

Thesis type




Issue date