De Novo Design, Synthesis, and Biological Evaluation of 3,4-Disubstituted Pyrrolidine Sulfonamides as Potent and Selective Glycine Transporter 1 Competitive Inhibitors

Abstract

The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders associated with hypofunction of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. Herein, we describe the synthesis and biological evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chemical structure to drug-drug interaction (DDI) and bioactivation was mechanistically investigated. Murine studies were strategically incorporated into the screening funnel to provide early assessments of in vivo target occupancy (TO) by ex vivo binding studies. Advanced compounds derived from iterative structure-activity relationship (SAR) studies possessed high potency in ex vivo binding studies and good brain penetration, promising preliminary in vivo efficacy, acceptable preclinical pharmacokinetics, and manageable DDI and bioactivation liabilities.

Automated De Novo Drug Design: Are We Nearly There Yet?

“…Also,a utomated methods must be employed, not manual de novo design (Note:not all de novo design in the literature is automated, it can be used as asynonym for knowledge-based design by medicinal chemists). [21,22]…”

Sulfonamides: Synthesis and the recent applications in Medicinal Chemistry

“…Naphthalene-1-sulfonamide derivatives were lately evolved as potent and selective inhibitors of fatty acid binding protein 4, a capability therapeutic target for diabetes and atherosclerosis [195]. Novel design and synthesis of 3,4-disubstituted pyrrolidone sulfonamide derivatives were additionally stated.The compounds were found to be selective and potent competitive inhibitors of glycine transporter [196] and promising applicants for drug improvement to deal with schizophrenia and different mental ailments. In another observe, sulfone pyrrolidine sulfonamides have been utilized as antagonists of temporary receptor capacity vallinoid-4 (TRPV4) with in vivo activity in a pulmonary edema model [197].…”

Automated De Novo Drug Design: Are We Nearly There Yet?

“…Only examples in which designed compounds have their activities verified by synthesis and assays are included since we consider this a non‐negotiable criterion for validation of de novo design methods. Also, automated methods must be employed, not manual de novo design (Note: not all de novo design in the literature is automated, it can be used as a synonym for knowledge‐based design by medicinal chemists) …”