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GPCR LIBRARIES

 

 

Structure of the first C2 domain from human KIAA1005 protein (mu opioid receptor)

(20 conformations / 1 conformation / schematic representation)

G-protein coupled receptors are the major family of receptors at the cell surface. They are activated by many ligands including hormones, peptides, aminoacids, ions and photons to influence signal transduction. Numerous diseases are caused by GPCRs polymorphisms or mutations. This makes them ideal therapeutic targets. An estimated 50 % of the modern drugs modulate the activity of a GPCR. About 350 GPCRs are encoded by the human genome, 150 of them having unknown function.

Most of the GPCRs share the architecture of the seven transmembrane domains which probably assume the basic functions. It is thus believed that the specificity is related to the differences on the N-terminal and C-terminal chains and on the intra- and extra-cellular loops. Those differences are used for the classification of the GPCRs, the largest group being the Class A (Rhodopsin-like), further divided into 19 subgroups.

The mechanism of action was traditionally considered to be monomeric with a one-to-one ratio of the receptor and the G-protein. Recent works demonstrated the existence of an oligomeric process that completely changed the way of designing inhibitors. Parallel synthesis is an opportunity to introduce new scaffolds to investigate those different processes.

ALKOXYNICOTINAMIDE LIBRARY
ALKOXYNICOTINAMIDE LIBRARY

• privileged structures for aminergic and peptidergic GPCRs and phosphodiesterases
• original 2- and 6-nicotinic intermediates with good diversity
• high degree of druglikeness
• library based on 24 intermediates

ARYLOXYPROPYLAMINE LIBRARY
ARYLOXYPROPYLAMINE LIBRARY

• versatile privileged scaffold for GPCR and CNS targets
• in vivo activities reported for related compounds, especially in CNS
• focused library enabling exploration / establishment of preliminary SAR
• open scaffold from a structural point of view
• library based on 18 intermediates

PYRAZOLE PROPIONAMIDE LIBRARY
PYRAZOLE PROPIONAMIDE LIBRARY

• diverse exploration of pyrazole-4-propionamides
• privileged structures for aminergic and peptidergic GPCRs and NSAIDs
• flexible structures to optimize position in the active sites
• library based on 10 intermediates

SPIROCHROMANONE LIBRARY
SPIROCHROMANONE LIBRARY

• privileged structure for GPCR and CNS targets
• conformational constraint of known GPCR pharmacophores
• experimental validation
• original scaffold enabling good diversity
• library based on 27 intermediates

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