Ana I. Mateo

4-Alkylidenyl glutamic acids, potent and selective GluR5 agonists

Twenty-four 4-alkylidene glutamic acids were synthesised and tested as potential subtype selective GluR5 and 6 ligands. It was found that a critical size of alkylidene group gave potent and selective GluR5 receptor agonists. LY339624 had Kis of 0.0326 and >100 microM on GluR5 and 6 receptors, respectively.

Design, synthesis and structure-activity-relationship of 1,5-tetrahydronaphthyridines as CETP inhibitors.

This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.

GluK1 antagonists from 6-(tetrazolyl)phenyl decahydroisoquinoline derivatives: in vitro profile and in vivo analgesic efficacy.

We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.

Design and synthesis of new tetrahydroquinolines derivatives as CETP inhibitors

This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties.

GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models

The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.

Chronic inhibition of the MEK/ERK pathway fails to delay disease progression in a transgenic animal model of tauopathy

Background: Neurofibrillary tangles (NFT), one of the hallmarks of Alzheimer’s disease (AD), are composed of paired helical filaments (PHF) of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD.Methods:We have used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with early AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes pS202, pT231, pS235 and pS396/404) were measured in cell lysates using AlphaScreen assays. Results: GSK3a, GSK3b and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all 4 epitopes. Pathway analysis of all the ‘hits’ suggests the Ras family of GTPases (MAPK family) to be a key regulator of tau phosphorylation. Pathway analysis on subgroups of kinases reveals several mechanisms involved in regulating tau expression levels by inhibition or activation of translation.Conclusions: The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies.