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  • KPT-9274 australia In parallel we were also preparing

    2021-10-13

    In parallel, we were also preparing and evaluating other piperidine bioisosteres and modifications to – to further access additional novel intellectual property (IP) space. Modeling work suggested that 4-position homologated piperidines, as well as 3-position homologated azetidines overlapped favorably with –, and . Thus, chemistry was quickly developed to access these cores (). Starting from commercially available -Boc-azetidine-3-carboxylic KPT-9274 australia or -Boc-piperidine-4-carboxylic acid , conversion to the Weinreb amide and treatment with an aryl, heteroaryl or aliphatic Gringard reagent provided and , respectively. Condensation with hydroxylamine, reduction and acylation afforded amides and . Finally, removal of the Boc moiety and sulfonylation of the secondary amine led to putative, racemic GlyT1 inhibitor series and . As shown in , the homologated azetidine-based analogs were uniformly more potent than the corresponding homologated piperidine-based analogs , affording GlyT1 inhibitors with low nanomolar potency. While the 2,4-dichlorobenzamide was the most potent congener, other benzamides displayed a wide range of GlyT1 potency (GlyT1 ICs from 80 nM to 7μM). Moreover, in the azetidine series , the aryl/heteroaryl R moieties could be replaced with aliphatic groups and retain potency (R=Pr, GlyT1 IC=394nM; R=Pr, GlyT1 IC=185 nM; R=Pr, GlyT1 IC=253 nM), whereas the corresponding analogs in the piperidine series were inactive. Representative members from both and were evaluated for their effect on enzyme kinetics of [C]-glycine transport, and both were shown to be competitive with glycine, as well as selective versus GlyT2 (IC>30μM). Initial evaluation in our in vitro DMPK assays demonstrated that was stable in fortified rat liver microsomes (75% parent remaining at 90min), possessed a good unbound fraction in rat (=14%) and clean CYP profile (ICs>10μM). An oral plasma:brain level (PBL) study with oral dosing (10mg/kg p.o. in 0.5% methocellulose) of afforded a low Brain:Plasma of 0.11. SCF separation of the enantiomers led to the isolation of the two pure enantiomers, and one was quite active (IC=39 nM) while the other proved much weaker (IC=900nM). In consultation with the Johnston group, they developed an asymmetric synthesis of , via chiral proton catalysis of a secondary nitroalkane addition to an azomethine, and we were able to elucidate that the potent enantiomer had the ()-configuration. Overall, the low brain:plasma ratios of these series, , , and diminished enthusiasm; however, the scaffold hopping strategy again secured robust IP position for both the and series of GlyT1 inhibitors., In summary, we were able to successfully further scaffold hop from , originally derived at from a scaffold hopping exercise from and , and develop three new series for which US patents were granted without the need for an HTS campaign. This was critical, as the time required to perform a SPA-based HTS campaign and identify/optimize the hits would have required far more time and uncertain IP position in a highly crowded and competitive space. These new series retained the potency and selectivity of the advanced compounds from which they were derived, but did suffer from only modest CNS exposure. Finally, all of these new series displayed enantioselective inhibition of the GlyT1 transporter. Further refinements are in progress and will be reported in due course. Acknowledgments This work was supported by the NIH/NIMH under a National Cooperative Drug Discovery and Development grant U01 MH08795. D.J.S. is a recipient of a National Alliance for Research on Schizophrenia and Depression (NARSAD)–Dylan Tauber Young Investigator Award. Vanderbilt is a member of the MLPCN and houses the Vanderbilt Specialized Chemistry Center for Accelerated Probe Development supported by U54 MH084659. The support of William K. Warren, Jr. who funded the William K. Warren, Jr. Chair in Medicine (to C.W.L.) is gratefully acknowledged.