GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement

Benzodiazepine site agonists (such as diazepam) are well-known to impair cognition. Since benzodiazepines exert their effects via modulation of α1-, α2-, α3- and α5-containing GABA(A) receptors, the cognition-impairing effects of diazepam must be associated with one or several of these subtypes. Of these different subtypes, α5-containing GABA(A) receptors represent an attractive option as the "cognition" subtype based upon the preferential localization of these receptors within the hippocampus and the well-established role of the hippocampus in learning and memory. As a result, it is hypothesized that an inverse agonist selective for the α5 subtype should enhance cognition. For example, L-655708, a partial inverse agonist with 50-100-fold higher affinity for the α5 relative to the α1, α2 and α3 subtypes of GABA(A) receptors, enhanced cognitive performance in rats. Unfortunately, however, pharmacokinetic properties of this compound prevented it being developed further. In order to try achieve binding selectivity in a series structurally distinct from the imidazobenzodiazepines, the group at Merck, Sharp & Dohme commenced studies within the triazolopyridazine series. Although a degree of binding selectivity could be achieved (a maximum of 22-125-fold for α5 versus α1, α2 or α3) this approach was dropped in favour of a strategy to identify compounds with either a combination of selective affinity and selective efficacy or purely selective efficacy. With respect to the former, screening of the Merck chemical collection identified a novel, moderately α5-binding selective thiophene series and further optimization of this series produced MRK-536, which demonstrated a modest α5 binding selectivity (~10-fold) as well as α5-efficacy selectivity. However, the structure-activity relationship within this and the analogous tetralone series proved unpredictable and these series were not pursued further. The success of the selective efficacy approach on the α2/α3-selective agonist project led a similar paradigm being adopted for the α5 project. The starting point for this strategy was the triazolopyridazine 3 which, like MRK-536, possessed a degree of both α5 binding- and efficacy-selectivity. By changing the core from a triazolopyridazine to a triazolophthalazine structure, α5 binding selectivity was lost but with subsequent optimization, compounds with the desired profile (low or antagonist efficacy at the α1, α2 and α3 subtypes and marked inverse agonism at α5-containing receptors) could be achieved, allowing the clinical candidate α5IA as well as the structurally-related pharmacological tool compound α5IA-II to be identified. By appending features of the prototypic α2/α3-selective triazolopyridazine L-838417 (t-butyl and 1,2,4 triazole) along with the isoxazole of α5IA to a pyrazolotriazine core, an additional clinical candidate, MRK-016, was identified. Finally, a degree of α5 efficacy selectivity was achieved the pyridazine series but metabolic instability within this chemotype limited its further optimization. Overall, these studies demonstrate the feasibility of adopting a selective efficacy approach in the identification of α5 selective GABA(A) receptor inverse agonists.