Partnership between small biotech and big pharma.

The process involved in the identification and development of novel breakthrough medicines at big pharma has recently undergone significant changes, in part because of the extraordinary complexity that is associated with tackling diseases of high unmet need, and also because of the increasingly demanding requirements that have been placed on the pharmaceutical industry by investors and regulatory authorities. In addition, big pharma no longer have a monopoly on the tools and enabling technologies that are required to identify and discover new drugs, as many biotech companies now also have these capabilities. As a result, researchers at biotech companies are able to identify credible drug leads, as well as compounds that have the potential to become marketed medicinal products. This diversification of companies that are involved in drug discovery and development has in turn led to increased partnering interactions between the biotech sector and big pharma. This article examines how Merck and Co Inc, which has historically relied on a combination of internal scientific research and licensed products, has poised itself to become further engaged in partnering with biotech companies, as well as academic institutions, to increase the probability of success associated with identifying novel medicines to treat unmet medical needs--particularly in areas such as central nervous system disorders, obesity/metabolic diseases, atheroma and cancer, and also to cultivate its cardiovascular, respiratory, arthritis, bone, ophthalmology and infectious disease franchises.

Aminoalkyl phenyl sulfones--a novel series of 5-HT7 receptor ligands.

A novel series of 5-HT(7) receptor ligands has been identified and evaluated, providing compounds showing a broad spectrum of functional activities and good selectivity over selected receptors and ion channels.

Thiazoles and thiopyridines: novel series of high affinity h5HT(7) ligands.

A series of thiazole based 5HT(7) ligands has been identified from screening. Optimisation of the pendent aryl group and modification of the core gave a related series of high affinity, selective thiopyridine based 5HT(7) ligands, the most active of which behaves as a partial agonist.

Native and recombinant human Edg4 receptor-mediated Ca(2+) signalling.

We have developed an assay system suitable for assessment of compound action on the Edg4 subtype of the widely expressed lysophosphatidic acid (LPA)-responsive Edg receptor family. Edg4 was stably overexpressed in the rat hepatoma cell line Rh 7777, and a Ca(2+)-based FLIPR assay developed for measurement of functional responses. In order to investigate the mechanisms linking Edg4 activation to cytosolic Ca(2+) elevation, we have also studied LPA signalling in a human neuroblastoma cell line that endogenously expresses Edg4. LPA responses displayed similar kinetics and potency in the two cell lines. The Ca(2+) signal generated by activation of LPA-sensitive receptors in these cells is mediated primarily by endoplasmic reticulum. However, there is a substantial inhibition of the LPA response by FCCP, indicating that mitochondria also play a key role in the LPA response. Partial inhibition of the response by cyclosporin A could indicate an active Ca(2+) release role for mitochondria in the LPA response. The inositol 1,4,5-triphosphate receptor antagonist 2-aminoethyl diphenyl borate markedly inhibits, but does not abolish, the Ca(2+) response to LPA, suggesting further complexity to the signalling pathways activated by Edg receptors. In comparing Edg signalling in recombinant and native cells, there is a striking overall similarity in receptor expression pattern, agonist potency, and the effect of modulators on the Ca(2+) response. This indicates that the Edg4-overexpressing Rh7777 cell line is a very useful model system for studying receptor pharmacology and signalling mechanisms, and for investigating the Edg4 receptor's downstream effects.