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  • br Significant efforts are currently focused

    2021-10-19


    Significant efforts are currently focused on non-dopaminergic strategies to address the unmet medical needs in schizophrenia, and targeting -methyl--aspartate (NMDA) cysteine protease hypofunction has garnered a great deal of attention., , Elevation of synaptic glycine levels near NMDA-containing synapses, by inhibition of the glycine transporter type 1 (GlyT1), has proven to be a viable mechanism for achieving efficacy in multiple preclinical models of schizophrenia with a diverse array of GlyT1 chemotypes., , , , , More recently, Roche reported Phase II clinical efficacy with their GlyT1 inhibitor (RG6178) in improving the negative symptoms in patients with schizophrenia, a symptom cluster largely unmet with available antipsychotic agents, that re-ignited the field. Furthermore, new data suggests roles for GlyT1 inhibition in alcohol dependence, addiction and pain. Based on these data, the late-stage clinical status of GlyT1, and the crowded intellectual property space,, , , , , we elected to attempt to develop novel chemical space by scaffold hopping, a strategy we previously employed successfully for T-Type calcium channel inhibitors, to accelerate a fast follower GlyT1 inhibitor program. For this exercise, we were attracted to the GlyT1 inhibitors reported from both Merck, represented by and ,, , and Pfizer’s (), as they possessed potent GlyT1 inhibition with good DMPK profiles and efficacy in preclinical models;, , , moreover, homology and overlap was noted between these otherwise disparate chemotypes. Our initial approach was to replace the central piperidine core of and , , with the [3.1.0] bicyclic ring system found in , to arrive at analogs such as (). Synthetically, analogs were arrived at via a seven step route in low (∼4%) overall yield. Starting from commercially available (1,5,6)-3--butyl 6-ethyl 3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate , two step conversion to the primary carboxamide proceeded smoothly, followed by treatment with cyanuric chloride to afford the nitrile (). Deprotonation with KHMDS and alkylation with cyclopropyl methylbromide in toluene at 0°C provided in 20% yield, as a single diastereomer (stereochemical assignment based on literature precedent and NOE studies). TFA-mediated removal of the Boc group, followed by sulfonylation with various sulfonyl chlorides, generated congeners . Finally, ‘Raney’ Ni reduction of the nitrile and subsequent acylation with 2,4-dichlorobenzoyl chloride delivered analogs . The initial 10-membered library of analogs displayed somewhat unexpected SAR, with a significant diminution in potency relative to the piperdine-based GlyT1 inhibitors and ()., , For example, (GlyT1 IC=1.3μM), the direct analog of (GlyT1 IC=26nM), lost 50-fold in potency, and (GlyT1 IC=360nM), the -propyl congener of (GlyT1 IC=2.4nM), lost ∼150-fold. A trend towards increased activity resulted with a cyclopropyl methyl sulfonamide (GlyT1 IC=230nM), but all other modifications, including aryl ( and ) and heteroaryl sulfonamides ( and ) led to significant loss in GlyT1 potency. However, all analogs retained high selectivity versus GlyT2 (IC >30μM) and preliminary in vitro DMPK profiling indicated that this core retained the favorable disposition properties of – ( 2–4%, IC >10μM vs CYP3A4, 2D6, 1A2 and 2C9). Substitution of the 6-cyclopropyl methyl group in with either phenyl or 2-pyridyl moieties, also led to inactive analogs (GlyT1 IC >30μM) and represented a divergence from the SAR of the piperidine series and ., , Analogs of where the optimal sulfonamides were maintained ( and ), but the substitution on the benzamide moiety was varied, once again led to a large diminution in GlyT1 potency (data not shown). As we began to assess and consider the data generated thus far, we were attracted to the -methyl imidazole moiety of Pfizer’s , and with simple models could achieve an orientation in which the -methyl imidazole moiety could fill the same space as the alkyl sulfonamides in and . Thus, we hypothesized that -methylimidazole sulfonamide congeners might enhance GlyT1 potency in analogs .