The Development of Dual-Tropic CXCR4/CCR5 HIV-1 Entry Inhibitors Open Access

Urbano, Catherine (Spring 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/s1784k75z?locale=en
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Abstract

The CDC estimates that 1.2 million Americans aged 13 years and older are living with HIV infection, however only 87% are diagnosed and only a shocking 36% are engaged in treatment. Despite 26+ HIV drug therapies on the market, drug resistance, affordability, and side effects are still major concerns. To combat these obstacles, our research specifically focused on designing a singular compound with dual CCR5 and CXCR4 activity. From prior work conducted in our lab, we identified a compound composed of a pyrazole-piperidine core that inhibited both receptors. After an extensive SAR study, compound 11 was identified as the lead target. In addition to containing dual-tropic activity, 11 also demonstrated an off-target effect against HIV reverse transcriptase. Saturated transfer difference NMR studies indicated that compound 22 would remove reverse transcriptase activity. Our efforts described herein focus on understanding the functional group tolerance of the A-ring, but also efforts toward eliminating reverse transcriptase activity via the synthesis of 22.

Table of Contents

Introduction....................................................................................................................................1

Results............................................................................................................................................6

             Identification of Lead Compound.......................................................................................6

             Overview of SAR on A, B, C, and D-rings.............................................................................8

             Synthesis of Novel A-ring Derivatives...............................................................................11

             Synthesis of a Novel C-Ring Derivative: compound 22.....................................................13

Conclusion....................................................................................................................................24

Experimentals...............................................................................................................................26

References....................................................................................................................................32

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