The amino acid glutamate is the major excitatory neurotransmitter in the mammalian brain exerting its effects through ionotropic and metabotropic glutamate receptors.  The family of metabotropic glutamate receptors is divided into eight subtypes and classified into three groups based on their sequence homology, signal transduction and pharmacology. Group I (mGluR1 and 5) are positively coupled to phospholipase C whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7 and 8) receptors are negatively coupled to adenyl cyclase.  Due to the high degree of homology between group II mGluR's, very few selective agonists for mGluR2 vs. mGluR3 have been discovered. Therefore, another strategy entails finding a positive allosteric modulator (PAM) of the mGlu2 receptor, which does not bind to the glutamate binding site, but rather binds to the transmembrane domain and increases the affinity of the mGlu2 receptor for glutamate. Allosteric potentiators of mGluR2 have been shown to inhibit glutamate neurotransmisson under conditions of enhanced, but not normal glutamate activity with potential therapeutic use in certain CNS conditions like anxiety, schizophrenia and pain/migraine.  A high-throughput screen (HTS) identified the hydroxyacetophenone series as one class of compounds acting as mGluR2 PAMs.  Moreover, these compounds also demonstrated antagonist activity at the CysLT1 (LTD4) receptor and it was hypothesized that this dual combination of pharmacologies would prove beneficial as a treatment for migraine pain.  The SAR, ADME characteristics and in vivo pharmacology leading to the identification of clinical candidate LY2300559 possessing these dual pharmacologies will be presented.

Identification of a series of novel hydroxyacetophenones containing dual pharmacology at the mGluR2 (potentiator) and CysLT1 (antagonist): SAR, ADME properties and effects in an in vivo model of migraine

246th National Meeting (2013)

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