Abstract |
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i ( GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i ( GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
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Authors | Adrian Hall, Susan H Brown, Christopher Budd, Nicholas M Clayton, Gerard M P Giblin, Paul Goldsmith, Thomas G Hayhow, David N Hurst, Alan Naylor, D Anthony Rawlings, Tiziana Scoccitti, Alexander W Wilson, Wendy J Winchester |
Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 19
Issue 2
Pg. 497-501
(Jan 15 2009)
ISSN: 1464-3405 [Electronic] England |
PMID | 19036582
(Publication Type: Journal Article)
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Chemical References |
- GSK345931A
- Ptger1 protein, mouse
- Ptger1 protein, rat
- Pyridines
- Receptors, Prostaglandin E
- Receptors, Prostaglandin E, EP1 Subtype
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Topics |
- Animals
- Drug Evaluation, Preclinical
- Inflammation
(drug therapy)
- Pain
(drug therapy)
- Pyridines
(chemistry, pharmacology, therapeutic use)
- Rats
- Receptors, Prostaglandin E
(antagonists & inhibitors)
- Receptors, Prostaglandin E, EP1 Subtype
- Structure-Activity Relationship
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