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  • During the course of our

    2019-11-06

    During the course of our research on mGlu PAMs,, the hydroxyacetophenone scaffold was found to possess dual mGlu PAM and CysLT1 antagonism activity, presumably as orthosteric antagonist (). There is currently an increasing interest in drug discovery to explore multitarget drugs or polypharmacology, approaches towards complex diseases such as neurological disorders. This approach suggests that a more effective drug can be developed by specifically modulating more than one target. In this paper, we describe the SAR efforts to systematically explore the chemical space of scaffold (domains depicted in ) and the corresponding impact on the dual pharmacological activity. Aiming to further assess efficacy, and aware of the potential impact of heterocycles, on pharmacokinetics (PK), we decided to focus the SAR on ligands containing pyridine rings in domains B and C. From this effort, a small set of compounds with different dual pharmacology profiles were selected for pharmacokinetic characterization and efficacy in the plasma protein extravasation (PPE) model of migraine. An initial assessment was focused on the regiochemistry of the tetrazole ring of domain D in regards to the ether linkage. To accelerate the lead generation effort, we performed this assessment in a couple of series (compounds – and –, ) thus evaluating simultaneously the regiochemistry between domains B and C. Examination of the profile for compounds – (domain B, -regiochemistry) indicated only slight differences in potency at either mGlu or CysLT1 between the regioisomers of the tetrazole, with all three compounds having activity at both targets in similar range (<500nM for most of compounds). For compounds – (domain B, -regiochemistry), we observed balanced activity across the two targets as well, however the series tended to be, in general, more potent at both targets relative to the series. The introduction of a carboxylic Vinpocetine receptor as a tetrazole replacement (compound vs. , series; vs. , series) seemed to lead to slight weaker mGlu activity. SAR exploration of the hydroxyacetophenone moiety (domain A) was conducted next. shows the activity for mGlu PAM and CysLT1 when different R substituents were incorporated. Reducing the steric bulk (methyl group , vs. propyl analog ) led to a ∼8-fold increase in CysLT1 antagonist activity (IC=24nM), and a modest effect (∼2-fold) in mGlu PAM activity. The introduction of electron withdrawing groups, i.e. Cl and CF, was tolerated or led to a significant enhancement in mGlu PAM activity relative to the corresponding propyl analog , in particular for CF analog () achieving single digit activity (IC=6nM, >15-fold increase). However, replacing the propyl group with either Cl or CF did not lead to significant increases in CysLT1 antagonist activity. Substitution of the propyl moiety with a fluoro (compound ) led to >1μM dual activity. The initial SAR conducted indicated that a pyridine ring was broadly tolerated in domain C so we assessed the impact of introducing a pyridine in domain B (). Exchanging the pyridine ring between domains ( vs. ) led to a balanced profile at both receptors. Maintaining phenyl rings in both domains () elicited a detrimental effect in CysLT1 activity (IC>1μM), albeit generating an interesting tool compound with a preferred mGlu PAM profile. Having generated compounds with distinctive dual pharmacological profiles, it became important to assess the pharmacokinetic properties of this series to ultimately connect the polypharmacology to a PK/PD setting. Compounds , , and were selected for ADME studies in rat (). All three compounds maintained an acceptable pharmacokinetic profile in rats that warranted oral testing in the rat plasma protein extravasation (PPE) model of migraine. The neurogenic dural plasma protein extravasation (PPE) model, which examines the inhibition of neurotransmitter release from the peripheral branches of trigeminal sensory neurons following activation of the trigeminal nerve, is a widely accepted model of acute migraine., Compounds with demonstrated clinical efficacy, such as sumatriptan, zolmitriptan, ergotamine, and rizatriptan, were effective at blocking plasma extravasation in this model.,