Contemporary Accounts in Drug Discovery and Development

4 Chapter 6Table 6.1 Binding affinities and functional agonist or antagonist responses...Table 6.2 Residues interacting with L‐Glu in the orthosteric site.Table 6.3 Mean plasma pharmacokinetic parameters for 11following single i....Table 6.4 Mean plasma and cerebrospinal fluid concentrations of 11followin...Table 6.5 Mean plasma pharmacokinetic parameters of 19following single i.v...Table 6.6 Mean plasma and cerebrospinal fluid concentrations of 19at 1 h f...Table 6.7 FLIPR agonist responses produced by 11in AV12 cells transiently ...Table 6.8 Summary of plasma pharmacokinetic parameters of 11after single d...Table 6.9 Summary of plasma and cerebrospinal fluid pharmacokinetic paramet...Table 6.10 Primary statistical analysis of BOLD response to ketamine challe...

5 Chapter 7Table 7.1 In vitro and in vivo parameters for taselisib and GastroPlus expe...

6 Chapter 8Table 8.1 Off‐DNA hit confirmation.Table 8.2 SAR at cycle 4.Table 8.3 SAR at cycle 3.Table 8.4 SAR at cycle 2.Table 8.5 P450 inhibition summary.Table 8.6 Rat PK data summary for selected compounds.

7 Chapter 9Table 9.1 Number of unique GPCR complexes.

8 Chapter 10Table 10.1 SAR on core substitution.Table 10.2 Variation of R 2with fixed R 3and R 6.Table 10.3 BP NDof [ 11C] 17, [ 11C] 21and [ 11C] 22compared with [ 11C] 10.Table 10.4 Key parameters for tracer candidates.Table 10.5 Examples of fluorine‐containing PET tracer candidates.Table 10.6 P‐gp ratios in human, monkey, and rat at 1 and 0.1 μM.Table 10.7 B maxand K dvalues for [ 3H] 10in rhesus monkey and human striatu...Table 10.8 Test–retest variability for [ 11C] 10in rhesus monkey a.

9 Chapter 11Table 11.1 Comparison of PROTACs with other therapeutics.Table 11.2 Examples of PROTACs.Table 11.3 Pharmacokinetic data for exemplary PROTACs.Table 11.4 Phase I PK data for ARV‐110.Table 11.5 Preclinical efficacious exposure range of ARV‐110 in mouse.Table 11.6 Preclinical efficacious exposure range of ARV‐471 in mouse.Table 11.7 Phase I PK data for ARV‐471.

10 Chapter 12Table 12.1 Some FDA approved peptide drugs (2005–2019) exemplifying their th...Table 12.2 Some computational, biophysical and biological screening tools u...

11 Chapter 13Table 13.1 ADCs with SG‐3199 (payload) in clinical trials.Table 13.2 ADCs with SG‐1882 (payload) in clinical trials.Table 13.3 ADCs with IGN‐based payloads in clinical trials.Table 13.4 Twelve FDA approved ADCs.

12 Chapter 14Table 14.1 Preclinical PK profiles of olaparib in rat and dog.Table 14.2 Pharmacokinetic parameters of bevacizumab with intravenous dosing...Table 14.3 Pharmacokinetic profiles of olaparib dosed twice daily (b.i.d.) i...Table 14.4 Summary of clinical outcome of PORLA‐1 phase 3 clinical trial [11...Table 14.5 The most common adverse events and the incidence of associated gr...Table 14.6 in vitro activity of ceftazidime–avibactam against selected Gram‐...Table 14.7 Summary of in vivo study results of the ceftazidime and vibactam ...Table 14.8 Single rising dose PK profiles of ceftazidime and avibactam alone...Table 14.9 Single and multiple dose PK profiles of ceftazidime (2000 mg) in ...Table 14.10 Clinical response of ceftazidime and avibactam combination for c...Table 14.11 Clinical response of ceftazidime and avibactam combination plus ...Table 14.12 Percentages of phase 2 ceftazidime/avibactam treatment‐emergent ...Table 14.13 Dosage recommendations for the ceftazidime and avibactam combina...Table 14.14 Primary and secondary efficacy endpoints in mMITT population.Table 14.15 Safety data in safety population up to late follow‐up.Table 14.16 Clinical response in the REPRISE trial ain mMITT population at t...Table 14.17 Clinical cure rate in the RECLAIM 1 and 2 clinical trials.Table 14.18 Clinical cure rate of ceftazidime–avibactam plus metronidazole c...Table 14.19 Clinical cure rate of ceftazidime–avibactam compared with merope...Table 14.20 Per‐pathogen clinical cure rates and per‐patient microbiological...

13 Chapter 15Table 15.1 BinaxNOWTM COVID‐19 Ag Card performance within seven days of symp...Table 15.2 in vitro antiviral activity of remdesivir.Table 15.3 Overall outcome of phase 3 trial carried out by NIAID (NCT0428070...Table 15.4 Key efficacy and safety results from the SIMPLE1 study.Table 15.5 Difference versus placebo of the meantime‐weighted‐average change...Table 15.6 Difference versus placebo of the viral load reduction through day...Table 15.7 Impact of dexamethasone on mortality of hospitalized patients wit...

1 Chapter 2 Figure 2.1 (a) An overlay of ND‐022 with the natural product soraphen and (b... Figure 2.2 Structures of ND‐022 and ND‐630. Figure 2.3 Superimposed crystal structures of TYK2, JAK1, JAK2, and JAK3 coc... Figure 2.4 (a) Inhibitors known to bind to the switch‐II pocket of KRAS G12C.... Figure 2.5 Correlation of experimental and calculated binding activity (∂ G ) ... Figure 2.6 Structures of initial hit and lead compound [130].

2 Chapter 3 Figure 3.1 sGC stimulator vericiguat. Figure 3.2 The NO/sGC signaling and natriuretic peptide/pGC signaling with m... Figure 3.3 Recurrent acute events contribute to heart failure progression. W... Figure 3.4 sGC stimulator riociguat. Scheme 3.1 Early days synthesis of vericiguat 2. Scheme 3.2 High yielding route to trisamine 24. Scheme 3.3 Scale‐up synthesis of iodide 21. Scheme 3.4 Development route to key intermediate 25. Scheme 3.5 Optimized scheme for the synthesis of acrylaldehyde derivative 35 Figure 3.5 Concentration‐dependent effects of vericiguat and NO (DEA/NO) on ... Figure 3.6 Relationship between vericiguat PK and (a) HR over one minute, (b... Figure 3.7 Pharmacokinetics of vericiguat in special populations. Figure 3.8 Effects of other drugs on the pharmacokinetics of vericiguat. Figure 3.9 Effects of vericiguat on the pharmacokinetics of other drugs [44]...

3 Chapter 4 Figure 4.1 The amyloid hypothesis of Aβ aggregation leading to the developme... Figure 4.2 Schematic illustration of APP process and generation of Aβ peptid... Figure 4.3 γ‐secretase enzymatic complex and its processing of the C99 subst... Figure 4.4 Initial SAR development of the tetrahydroquinoline and 2,6‐disubs... Figure 4.5 The SAR leading to the discovery of SCH 697466. Figure 4.6 A 40 levels expressed as a percent of vehicle in plasma, cortex,... Figure 4.7 The design of tricyclic sulfone γ‐secretase inhibitors. Figure 4.8 SAR evolution of the tricyclic sulfone GSI inhibitors. Figure 4.9 Structures of representative GSIs that were halted in clinical tr... Figure 4.10 Stepwise cleavage model for Aβ generation and potential effect o... Figure 4.11 Structure of representative NSAID GSMs and non‐NSAID GSMs. Figure 4.12 Conformational constraint design leading to the identification o... Figure 4.13 SAR development of the pyrazolopyridine series. Figure 4.14 The rational design of oxadiazoline GSMs. Figure 4.15 SAR development of oxadiazoline series and the design of oxadiaz... Figure 4.16 Initial SAR comparison between oxadiazoline and oxadiazine serie... Figure 4.17 Lead compounds from oxadiazoline, oxadiazine, and oxadiazepine s... Figure 4.18 Mass spectrometric analysis of Aβ peptides generated from HEK293 Figure 4.19 Aβ total, Aβ 40, and Aβ 42in (a) plasma and (b) CSF, and Aβ 40and ... Figure 4.20 Structures of representative clinical stage GSMs. Figure 4.21 Structure of BACE1 in complex with inhibitor OM99‐2 (PDB code: 1... Figure 4.22 Structures of representative BACE1 inhibitors entered into clini...