Researchers led by Martin Watterson at Northwestern University in Chicago, with colleagues near Strasbourg, France, have synthesized a series of small chemicals that could become the starting point for a drug development effort aimed at inhibiting inflammatory changes in glial cells without affecting inflammation elsewhere in the body. The paper also suggests a signal transduction pathway that might be a suitable target in trying to design glia-specific anti-inflammatory drugs. The paper was published online last week and will appear in the January 31 print edition of the Journal of Medicinal Chemistry.
These chemicals are 3-amino-6-phenyl-pyridazine derivatives, heterocyclic aromatics whose activity are reflected in what the authors call Compound 1. It inhibits the production of interleukin-1β (IL-1β ), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in cultured glial cells that were stimulated by treatment with Aβ1-42, an AβPP cleavage product shown to be neurotoxic. The study rests on the hypothesis that chronically activated glia produce excessive amounts of proinflammatory cytokines such as Il-1β, as well as oxidative-stress-related enzymes and acute-phase proteins, and that those together create an inflammatory state that damages neurons and spurs the onset of dementia. (See also polymorphism story below.)
Epidemiological results, though mixed, appear to support this notion in that non-steroidal antiinflammatory drugs (NSAIDs) can stem or slow AD (see related news item). However, currently available NSAIDs act systemically. Watterson's group has for the last three years tried to find compounds that would selectively inhibit glial signal transduction pathways leading to iNOS generation (Mirzoeva S. et al., 1999). They have focused on modulating glial-specific isoforms of calmodulin-dependent kinases (CaMKs). Yet the compounds they studied previously were analogs of natural products, which are generally too complex for the quick synthesis medicinal chemists require as they churn out derivatives to refine drug leads.
The present compound is different. It is based on a 1-(2-pyrimidyl) piperazine scaffold, a structure that can be manipulated easily and that is already present in other CNS-active compounds. In activated glia, Compound 1 inhibits Il-1β and iNOS production but leaves unaffected other glial functions, such as GFAP and glial apoE and COX-2 production.
While Watterson's group did not prove a definitive mechanism of action for their compound, further experiments suggest that it inhibits CaMKII but not p38 MAPK, which has been implicated in AD (Zhu X. et al. 2001) and is the target of drugs currently under development for rheumatoid arthritis. "We are especially interested in moving the effective concentration of Compound 1 lower while retaining selectivity and in extending the results to animal models of disease," said Watterson. The scientists hope to collaborate with industry to develop this early research further.—Gabrielle Strobel
- Mirzoeva S, Koppal T, Petrova TV, Lukas TJ, Watterson DM, Van Eldik LJ. Screening in a cell-based assay for inhibitors of microglial nitric oxide production reveals calmodulin-regulated protein kinases as potential drug discovery targets. Brain Res. 1999 Oct 9;844(1-2):126-34. PubMed.
- Zhu X, Rottkamp CA, Hartzler A, Sun Z, Takeda A, Boux H, Shimohama S, Perry G, Smith MA. Activation of MKK6, an upstream activator of p38, in Alzheimer's disease. J Neurochem. 2001 Oct;79(2):311-8. PubMed.
- Mirzoeva S, Sawkar A, Zasadzki M, Guo L, Velentza AV, Dunlap V, Bourguignon JJ, Ramstrom H, Haiech J, Van Eldik LJ, Watterson DM. Discovery of a 3-amino-6-phenyl-pyridazine derivative as a new synthetic antineuroinflammatory compound. J Med Chem. 2002 Jan 31;45(3):563-6. PubMed.