Based on the precedent with other GlyT inhibitors such as
Based on the precedent with other GlyT1 inhibitors such as , we evaluated both and for their ability to enhance prepulse inhibition (PPI) of the rodent acoustic startle response, a measure of sensorimotor gating known to be deficient in schizophrenic patients., In this Isochlorogenic acid B study (), both and were dosed orally at 30mg/kg (a dose known to engender >90% occupancy for ),, , and evaluated against four increasing prepulse intensities (70–88dB). Both and showed a statistically significant enhancement in prepulse inhibition at the 82 and 88dB prepulse intensities, with no effect on basal startle amplitude during no-stimulus trials. Thus, (VU0240391), derived from a scaffold-hopping exercise employing and , led to a novel [3.1.0]-based GlyT1 inhibitor with in vitro and in vivo properties comparable to other advanced GlyT1 inhibitors in short order, and for which a U.S. patent was issued.
In conclusion, we were able to scaffold hop and merge elements from both the Merck piperidine-based series of GlyT1 inhibitors, represented by and ,, , and Pfizer’s , into a novel, patented series of [3.1.0]-based -methylimidazole sulfonamides . Members of this series displayed exceptional GlyT1 potency, DMPK profiles, CNS penetration and comparable in vivo efficacy to advanced GlyT1 inhibitors without the need for an HTS to enable a fast-follower program. Additional scaffolds developed during the course of this scaffold-hopping program will be reported in due course.
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.
Mounting evidence suggests that the long established dopamine hyperfunction model for schizophrenia may inadequately account for the symptoms of this widespread disease., Although both typical and atypical antipsychotics target dopamine receptors and address the positive symptoms of schizophrenia (hallucinations, paranoia, and other delusions), negative symptoms (blunted affect, withdrawal) and cognitive deficits are not satisfactorily addressed with these treatments. A growing body of evidence indicates that hypofunction of -methyl--aspartate (NMDA) glutamatergic receptors may contribute to the etiology of the disease, yet direct agonists of NMDA receptors are neurotoxic. Glycine transporter 1 (GlyT1) has emerged as a promising alternative target due to existing reports of its potentiation of NMDA receptor activity by modulating the local concentrations of the NMDA co-agonist glycine. Recently, we disclosed potent and selective inhibitors of GlyT1 based on a 4,4-disubstituted piperidine lead structure. Exemplified by and (), these compounds exhibit potent (<10nM), selective (versus GlyT2, taurine transporter) inhibition of GlyT1 and selectively elevate glycine levels in rat prefrontal cortex., Furthermore, significantly enhances prepulse inhibition in DBA/2J mice without impairing basal startle amplitude indicating an antipsychotic effect without sedation. While and were effective in animal models after being dosed subcutaneously, they exhibit poor pharmacokinetic properties including low bioavailability. In addition to optimizing these properties to enable oral dosing, a further objective was developing compounds which demonstrate high transporter occupancy in vivo. Herein we report the achievement of these goals employing an iterative analogue library approach. A variety of strategies were pursued in order to improve the properties of and , including modification of the piperidine C4 substituent and substitution of the piperidine -sulfonamide. Aryl group replacements were prepared according to the route described in a. Quenching the lithium anion of nitrile with a variety of electrophiles (alkyl halides, epoxides), followed by Raney Ni-catalyzed reduction provided mono-Boc protected diamine . Acylation (PS-DCC, HOBt, or carboxylic acid chloride), acidic deprotection of the Boc group, and sulfonamide formation furnished the GlyT1 inhibitors listed in . Alternatively, the sequence could be modified (b) such that amide formation furnished the final products. Use of both routes enabled the facile generation of both amide and sulfonamide libraries; >300 analogues were prepared according to this procedure and selected data are presented in .