Discovery and Synthesis of Next Generation Chemokine Modulators with or without Concurrent HIV Reverse Transcriptase Inhibitory Activity Pubblico
Prosser, Anthony Robert (2015)
Abstract
Current HIV regimens require multiple antiviral drugs to arrest ongoing viral replication and restore immune function. These so-called "drug cocktails" work by utilizing several mechanisms of action to disrupt HIV replication. The drugs typically employed in this strategy include entry/fusion inhibitors, non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs/NRTIs), integrase inhibitors, and protease inhibitors. Unfortunately, these so-called "drug cocktails" come with significant financial burden, a continually emerging set of long term side effects, and the potential for resistance if not taken as prescribed, because addressing these problems is key to the eventual eradication of HIV herein disclosed are series of small molecule anti-virals with potential advantages in terms of resistance, cost, and side effects. More specifically, in Chapter 1 CXCR4 antagonists were pursued to potentially produce compounds with robust resistance profiles, by not allowing the virulent X4 tropic HIV viral strain to enter the cell. In Chapter 2 single agents that bind to combinations of CXCR4, CCR5 and HIV reverse transcriptase were also discovered and pursued to potentially decrease the cost and side effects of HIV treatment by combining multiple mechanisms of action in a single agent.
Table of Contents
Introduction: The Need to Develop More Anti-HIV Therapeutics 1
Chapter 1: CXCR4 Antagonists 10
1.1 CXCR4 as a Therapeutic Target 10
1.2 TIQ Modeling Targets - Chemistry 15
1.3 TIQ Modeling Targets - Results 28
1.4 TIQ Selectivity - Chemistry 30
1.5 TIQ Selectivity - Results 33
1.6 PIP SAR Targets - Chemistry 37
1.7 PIP SAR targets - Results 44
1.8 CXCR4 Experimentals 51
Chapter 2: Dual X4/R5 Modulators 130
2.1 CXCR4/CCR5 as a Therapeutic Target 130
2.2 Design of "Stitched" Dual X4/R5 Antagonists 135
2.3 "Stitched" Dual X4/R5 Antagonists - Results 140
2.4 Second Generation "Stitched" Dual X4/R5 Antagonists 141
2.5 Second Generation "Stitched" Dual X4/R5 Antagonists - Results 143
2.6 Virtual Screening and Discovery of Pyrazole Dual X4/R5 Series 145
2.7 Design of One-pot Methodology for the Conversion of Esters to Ketones 152
2.8 Initial Synthetic Studies on Dual-tropic Pyrazoles (D-Ring SAR) 159
2.9 Additional Synthetic Studies on Dual-tropic Pyrazoles (A, B, C-ring SAR) 171
2.10 Dual-tropic Pyrazole Series Conclusions 178
2.11 Dual-Tropic Experimental 186
Figures
Figure 0.1: Startling HIV statistics 1
Figure 0.2: Rate of AIDS diagnosis per year 2
Figure 0.3: The HIV life cycle 3
Figure 0.4: Mechanistic details of HIV entry 4
Figure 0.5: Additional mechanistic details of HIV entry 6
Figure 0.6: The Multinuclear Activation of Galactosidase Indicator (MAGI) assay 7
Figure 1.1: Potent CXCR4 antagonists and their activity against T-tropic HIV and signaling efficacy 12
Figure 1.2: Mutational data for AMD compounds in CXCR4 13
Figure 1.3: Synthetic targets based on first generation molecular modeling 15
Figure 1.4: Early modeling hypothesis for 2-napthyl 1 16
Figure 1.5: Early modeling hypothesis for di-butyl amine 4 17
Figure 1.6: Compounds designed with medicinal chemistry rationale to probe the CXCR4 selectivity profile 31
Figure 1.7: Initial modeling rationale for compound 45 32
Figure 1.8: Improved modeling rationale for compound 45's selectivity 37
Figure 1.9: Synthetic targets based on SAR principals on the PIP series. 38
Figure 1.10: Structural similarity of substitution at either piperazine. 39
Figure 1.11: Structural comparison of GSK compound to butyl-amine isosters 52 and 53. 39
Figure 1.12: Crystal structure and chiral assignment of 66. 42
Figure 2.1: Tropism independent small molecule entry inhibitors 130
Figure 2.2: Potent CCR5 antagonists 132
Figure 2.3: Anti-inflammatory effects of AMD3100 in mouse model 133
Figure 2.4: Compound stitching strategy in the pursuit of dual-active CCR5/CXCR4 antagonists 136
Figure 2.5: Design of "stitched"-compounds 4-7 137
Figure 2.6: Design of "stitched"-compounds 24-29 144
Figure 2.7: Example of Bayesian statistics 149
Figure 2.8: Virtual screening work flow and active hits 151
Figure 2.9: Retrosynthetic analysis and ring designation for screening hit 38 155
Figure 2.10: Correlation between hydrophobicity and toxicity 166
Figure 2.11: Binding of pyrazolo-piperidines to CCR5 (A/B) and CXCR4 (C/D) predicted by molecular modeling 170
Figure 2.12: Binding of pyrazolo-piperidines to HIV-RT predicted by molecular modeling 173
Figure 2.13: Potency gains from virtual screening hit to compound 92 179
Tables
Table 1.1: CYP450 and hERG Measurements 14
Table 1.2: Screening of Reaction Conditions 20
Table 1.3: Biological Testing of TIQ Modeling Compounds 28
Table 1.4: Biological Testing of TIQ Selectivity Targets 33
Table 1.5: Biological Testing of PIP R1 SAR Targets 44
Table 1.6: Biological Testing of PIP R2 SAR Targets 46
Table 2.1: Normal CXCR4 Expressing Cells and Analogous CXCR4 Expressing Tumor 134
Table 2.2: Anti-HIV and Antagonist Activity of "Stitched" Series 140
Table 2.3: Anti-HIV Activity of Second Generation "Stitched" Series 143
Table 2.4: Anti-HIV Activity of Pyrazole Screening Hits 149
Table 2.5: Screen of Reaction Conditions 154
Table 2.6: Reaction Scope Versus Piperidine Moiety 156
Table 2.7: Anti-HIV Data for D Ring Analogs 162
Table 2.8: Anti-HIV (% Inhibition) Data for D Ring Analogs 164
Table 2.9: Profiling of Lead D Ring Compounds 165
Table 2.10: R5 vs X4 vs RT activity for D Ring Analogs 168
Table 2.11: SAR of the A, B, and C rings 176
Table 2.12: Profiling of Two Sub-Series 178
Schemes
Scheme 1.1: Initial synthesis of TIQ compounds 18
Scheme 1.2: Synthesis of chiral building blocks 5 and 13 19
Scheme 1.3: Improved synthesis of TIQ series 21
Scheme 1.4: Synthesis of compounds 20 and 21 22
Scheme 1.5: Retrosynthetic design of target 3 and 4 23
Scheme 1.6: Synthesis of intermediate 31 in route to compounds 3 and 4 23
Scheme 1.7: Synthesis of target 3 and attempted synthesis of target 4 from intermediate 31. 25
Scheme 1.8: Proposed mechanism for side chain cleavage of compound 32 to form 9. 26
Scheme 1.9: Successful synthesis of target 4 from pyrrolidone 37 27
Scheme 1.10: Synthesis of target 43 and 44 31
Scheme 1.11: Synthesis of compound 45 31
Scheme 1.12: Synthesis and resolution of diastereomers 59 and 60 40
Scheme 1.13: Synthesis of Boc-protected advanced intermediates 63-70 41
Scheme 1.14: Synthesis of final products 71-78 43
Scheme 1.15: Synthesis of final products 93-102 44
Scheme 2.1: Synthesis and resolution of diastereomers 14 and 15 138
Scheme 2.2: Synthesis of final products 2-7 139
Scheme 2.3: Synthesis of final products 24 to 29 142
Scheme 2.4: Synthesis of screening hit 37 150
Scheme 2.5: Merck's synthesis of common intermediate 54 and an 153
alternative retrosynthetic analysis of precursor 57
Scheme 2.6: Conversion of intermediate 57 to target 54 157
Scheme 2.7: General route to D ring SAR 159
Scheme 2.8: Synthesis of modular intermediate 74 160
Scheme 2.9: Synthesis of compounds with various D rings 161
Scheme 2.10: Synthesis of compound 78 161
Scheme 2.11: Synthesis of C ring analogs 171
Scheme 2.12: Synthesis of compounds 116 and 117 172
Scheme 2.13: Synthesis of compound 121 173
Scheme 2.14: Synthesis of compounds 123 and 124 174
Scheme 2.15: Synthesis of compound 125 175
Scheme 2.16: Synthesis of compound 126 175
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