Abstract
Current advances in functional screening methodologies, medicinal chemistry,
and structure-based drug design have generated large increases in the number
and diversity of GPCR drug targets. Furthermore, basic research advances have
opened the way for still further exploitation of this target class. This
report:
- Explores current and likely consequences of recent advances concerning
GPCR x-ray structures, allosteric interactions, multimerization, and
functional selectivity;
- Extensively tabulates marketed drugs and compounds in development arranged
by receptor type and subtype;
- Presents in-depth interviews with recognized experts in the field.
G protein-coupled receptors (GPCRs) are popular drug targets, accounting for
about one-third of approved drugs and many hundreds of drugs currently in
development. Yet one can easily argue that the pharmacologic potential of
GPCRs is far from exhausted. Currently approved drugs address only a few
GPCRs. Technologic and scientific advances have resulted in R&D pipelines that
target a great many more GPCRs than are represented among currently marketed
products. In this report, we examine newer technologies used in GPCR
pharmacology.
Furthermore, the evolution of GPCR pharmacology is far from over. Basic
researchers have made a number of exciting and relevant discoveries in the
past decade, and these have already begun to make important contributions to
drug discovery. GPCRs: Dawn of a New Era? examines the current state of basic
research, featuring key developments with the potential to favorably impact
future drug discovery.
We consider the exciting area of allosteric modulation, which has already
yielded two marketed drugs and promises many more, some with capabilities
heretofore inaccessible. We also examine two other areas in basic research
that promise to have significant impact on the field: functional selectivity
and the role of homo- and heterodimers in GPCR function. Another basic
research advance, described herein, has, arguably, the greatest potential for
advancing GPCR pharmacology. Until this year, drug discovery scientists had
available to them only a single high-resolution x-ray crystallographic
structure of a GPCR. That was for rhodopsin, which is atypical from the drug
discovery perspective. Two relevant structures have become available, thus
energizing the GPCR structure-based drug design community.
GPCRs: Dawn of a New Era? then examines trends in applied GPCR research before
turning to a thorough presentation and analysis of marketed GPCR-based drugs
and of compounds currently in development or registration. We consider all
GPCR types and subtypes that are the subject of approved drugs or pipeline
candidates. The report spotlights numerous small pharmaceutical companies,
which tend to push the limits of GPCR pharmacology by attacking more targets
and by attempting to apply cutting-edge concepts derived from basic research.
In addition, we present a compendium of views on a variety of relevant
findings and issues in the field based on our extensive discussions with GPCR
experts.
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