Contemporary Accounts in Drug Discovery and Development

4 Chapter 5Figure 5.1 Chemical structures of lamivudine, adefovir, tenofovir, telbivudi...Figure 5.2 Schematic representation of the HBV life cycle.Figure 5.3 Two types of CpAMs (hexagon = capsid; circle = viral replication ...Figure 5.4 Crystal structure of Cp149 Y132A in complex with compound 14(hig...Figure 5.5 PK of compound 3in mice at various doses.Figure 5.6 Levels of HBV DNA in plasma (a) and liver (b) of HBV HDI mice upo...Figure 5.7 Evaluation of CYP3A4 induction of compound 3(RG7689) in healthy ...Figure 5.8 Utilization of conformational adjustment to influence CYP3A4 indu...Figure 5.9 Overlay of the cores of compounds 3and 15derived from the singl...Figure 5.10 Designing new analogues to mitigate CYP3A4 induction potential....Figure 5.11 Structures of RG7834 and reported HBsAg inhibitors.Figure 5.12 Hit generated from phenotypic screening against HBsAg.Figure 5.13 SAR exploration of the acid moiety.Figure 5.14 X‐ray structure of RG7834 ( S )‐ 47.Figure 5.15 Effect of RG7834 and ETV on HBV viral markers in HBV‐infected hu...Figure 5.16 Structure of Y3H‐DHQ.Figure 5.17 RSV fusion inhibitors in clinical development.Figure 5.18 The BAQ series originated from compound 54.Figure 5.19 Lead optimization resulting in the discovery of Ziresovir.Figure 5.20 in vivo reduction of RSV titer in mouse lung with RO‐0529. Femal...Figure 5.21 RO‐0529 inhibits the RSV F protein‐induced cell–cell fusion proc...

5 Chapter 6Figure 6.1 Cartoon representations of a subunit of NMDA receptors (a) and mG...Figure 6.2 A series of highly selective agonists for the group II mGlu recep...Figure 6.3 (a) Key interactions in the L‐Glu‐mGlu 3ATD structure (PDB ID: 2E...Figure 6.4 SAR evolution leading to discovery of mGlu 2subtype selective ago...Figure 6.5 (a) Agonist responses elicited by 11in human mGlu 2expressing AV...Figure 6.6 (a) Agonist response of 11in cortical membranes derived from wil...Figure 6.7 (a) Dose response of 11in the rat PCP locomotor activity assay. Figure 6.8 SAR evolution leading to discovery of the mGlu 3subtype selective...Figure 6.9 (a) Biphasic inhibition of Ca 2+oscillations by 19in cultured ra...Figure 6.10 Dose response of 19in the rat PCP locomotor activation assay. #Figure 6.11 (a) A protomer from the 3‐hmGlu 2ATD structure (PDB ID: 4XAQ) [4...Figure 6.12 (a) The ceiling formed by the Y144‐R271 pair in the 3‐hmGlu 2ATD ...Figure 6.13 (a) Crystal structure of the 11‐hmGlu 2ATD complex (PDB ID: 5CNJ)...Figure 6.14 (a) Key interactions between the C4α‐thiotriazolyl group and res...Figure 6.15 (a) Key interactions between the C4β‐benzamide group and residue...Figure 6.16 (a) FLIPR agonist responses produced by 11in hmGlu 2wild type a...Scheme 6.1 Divergent synthesis of 11and 19through a common intermediateFigure 6.17 (a) Plasma PK of active 11following p.o. dosing of prodrug 12i...Figure 6.18 Plasma and CSF PK of active 11after a single oral dose of 60 mg...Figure 6.19 (a) Dose response for 12in BOLD response to ketamine challenge ...

6 Chapter 7Figure 7.1 PI3K signaling pathway.Figure 7.2 Spectrum of PI3Kα inhibitor selectivity profiles of Genentech dev...Figure 7.3 (a) Structure and properties of HTS hit 1. (b) X‐ray structure of...Figure 7.4 Replacement of the N ‐methyl aniline amide with a 1‐isopropyl‐1,2,...Figure 7.5 Representative molecules spanning various oxepin scaffolds evalua...Figure 7.6 Structural differences contributing to selectivity for PI3Kα over...Figure 7.7 In vitro characterization of taselisib.Figure 7.8 Dose–response curves of fitted MCF7‐neo/HER2 tumor volumes in res...Figure 7.9 Simulations of plasma concentration–time profiles of taselisib in...

7 Chapter 8Figure 8.1 Encoding strategies: (a) DNA‐templated synthesis; (b) Vipergen Yo...Figure 8.2 Split‐and‐pool synthesis of DELs.Figure 8.3 Structure of DNA for DEL synthesis.Figure 8.4 Summary of the ELT selection process.Figure 8.5 (a) Synthesis of DELs A and B. (b) Synthesis of on‐DNA AUDA tool ...Figure 8.6 qPCR analysis measuring the yield of DEL‐A and on‐DNA AUDA in the...Figure 8.7 (a) DELs A and B. (b) Selection output with DEL‐B under different...Figure 8.8 Structure of ELT‐delivered asset 22and GSK2256294, a candidate m...

8 Chapter 9Figure 9.1 Number of total unique receptor complexes per year (www.gpcrdb.or...Figure 9.2 GPCR binding site computational analysis. Comparison of two Famil...Figure 9.3 CRF1R structures. In the left panels, the CRF1R inactive conforma...Figure 9.4 Importance of residence time for CRF1R negative allosteric modula...Figure 9.5 Crystal structure of the GCGR bound to MK‐0893 (PDB ID 5EE7) [45]...Figure 9.6 Molecular structures of agonist positive allosteric modulators co...Figure 9.7 Example of known GLP1R antagonist from Vanderbilt University [58,...Figure 9.8 Molecular structure of HTL26119.Figure 9.9 Protocol used to generate the VS databases of commercially availa...Figure 9.10 VS hits and initial lead. (a) The two‐dimensional structures of ...Figure 9.11 (a) (side view) and (b) (extracellular view) include a compariso...Figure 9.12 SAR highlights that resulted in the discovery of HTL26119. In th...

9 Chapter 10Figure 10.1 Profiles of compounds 1and 2.Figure 10.2 In vitro autoradiography with [ 3H] 2in mouse brain slices. (a)To...Figure 10.3 Profile of compound 5and SAR on the tail piece and northeastern...Figure 10.4 Comparison of time–activity curves and brain images among [ 11C] 2Figure 10.5 Chemical structure and in vitro properties of compound 10.Figure 10.6 Modifications on the core.Figure 10.7 Time–activity curves for [ 11C] 10and [ 11C] 22in monkey brain.Figure 10.8 Time–activity curves for [ 11C] 10and [ 18F] 23in monkey brain.Figure 10.9 (a) Snapshot of [ 11C] 22brain imaging in WT and P‐gp KO rat. (b)...Figure 10.10 (a) Scatter plot of PSA vs. rat P‐gp efflux ratio. Vertical lin...Figure 10.11 Scatter plot of rat PPB vs. HPLC Log D. Vertical line: X = 3.00...Figure 10.12 (a) Structures and in vitro properties of 31, 32,and 33.(b) P...Figure 10.13 (a) Summed image (0–90 minutes) of [ 11C] 10in rhesus monkey hig...Figure 10.14 PET image of [ 11C]MK‐6884 distribution in the brain of a health...

10 Chapter 11Figure 11.1 Regulation of protein drug targets by different approaches.Figure 11.2 Ubiquitination.Figure 11.3 Degradation of polyubiquitinated protein by the proteasome.Figure 11.4 The mechanism of action of PROTACs.Figure 11.5 PROTAC‐1.Figure 11.6 Peptide based PROTACs targeting AR (a) and ER (b).Figure 11.7 HIF‐1α based PROTAC.Figure 11.8 The first small molecule based PROTAC.Figure 11.9 VHL ligand based PROTAC (a) and CRBN ligand based PROTAC (b).Figure 11.10 (a) Structure of TrkA PhosphoProtac. (b) PhosphoPROTAC ErbB2PP P...Figure 11.11 Small molecule E3 ligase ligands.Figure 11.12 The crystal structure of the Brd4BD2‐MZ1‐VHL‐elonginC‐elonginB ...Figure 11.13 Hook effect. (a) PROTAC‐mediated ternary complex formation and ...Figure 11.14 The first all small molecule based PROTAC and verification of p...Figure 11.15 AR PROTACs based on the AR antagonist RU59063 and adamantly typ...Figure 11.16 AR PROTAC ARCC‐4. (a) Structure of ARCC‐4. (b) Degradation curv...Figure 11.17 AR degrader SNIPER(AR)‐51.Figure 11.18 (a) Structure of ARD‐69. (b) Pharmacodynamics (PD) study of ARD...Figure 11.19 Androgen receptor targeting PROTAC ARD‐61. (a) Structure of ARD...Figure 11.20 (a) Western blot analysis of ARV‐110 in LNCaP cells showing pot...Figure 11.21 Bio‐orthogonal strategy using click chemistry to assemble the l...Figure 11.22 Bio‐orthogonal strategy to generate the ERK‐CLIPTAC (click‐form...Figure 11.23 BET targeting PHOTAC‐I‐3 [31].Figure 11.24 FKBP123 targeting PHOTAC‐II‐5.Figure 11.25 Antibody‐PROTAC conjugate.Figure 11.26 ARV‐110 showed dose proportional human PK. (a) AUC 0–24of...Figure 11.27 Structure of ARV‐110.Figure 11.28 Human PK of ARV‐471. PO 30 mg, QD. ()Figure 11.29 Structure of ARV‐471.