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 4Figure 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 HEK293Figure 4.19 Aβtotal, Aβ40, and Aβ42 in (a) plasma and (b) CSF, and Aβ40 and ...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...
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 3 in 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 3 and 15 derived 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‐mGlu3 ATD structure (PDB ID: 2E...Figure 6.4 SAR evolution leading to discovery of mGlu2 subtype selective ago...Figure 6.5 (a) Agonist responses elicited by 11 in human mGlu2 expressing AV...Figure 6.6 (a) Agonist response of 11 in cortical membranes derived from wil...Figure 6.7 (a) Dose response of 11 in the rat PCP locomotor activity assay. Figure 6.8 SAR evolution leading to discovery of the mGlu3 subtype selective...Figure 6.9 (a) Biphasic inhibition of Ca2+ oscillations by 19 in cultured ra...Figure 6.10 Dose response of 19 in the rat PCP locomotor activation assay. # Figure 6.11 (a) A protomer from the 3‐hmGlu2 ATD structure (PDB ID: 4XAQ) [4...Figure 6.12 (a) The ceiling formed by the Y144‐R271 pair in the 3‐hmGlu2 ATD ...Figure 6.13 (a) Crystal structure of the 11‐hmGlu2 ATD 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 11 in hmGlu2 wild type a...Scheme 6.1 Divergent synthesis of 11 and 19 through a common intermediateFigure 6.17 (a) Plasma PK of active 11 following p.o. dosing of prodrug 12 i...Figure 6.18 Plasma and CSF PK of active 11 after a single oral dose of 60 mg...Figure 6.19 (a) Dose response for 12 in 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 22 and GSK2256294, a candidate