2. Academic Validation
  3. Discovery of novel SSRIs for a combination-treatment with pimavanserin

Discovery of novel SSRIs for a combination-treatment with pimavanserin

  • Bioorg Med Chem Lett. 2026 Aug:137:130662. doi: 10.1016/j.bmcl.2026.130662.
Annika Kers 1,  Bálint Gabos 2,  Sanjay Borhade 2,  Emelie Andersson 2,  Hanna Andersson 2,  Ulf Wellmar 2,  Mattias Jönsson 2,  Sofi Gummeson 2,  Klaus Dreisch 2,  Nima Rajabi 2,  Niklas Sköld 2,  Ricardo J Ferreira 2,  Marc R Azar 3,  John A Lowe 3rd 4,  Ethan S Burstein 5
Affiliations

Affiliations

  • 1 RG Discovery AB, Medicon Village, SE-223 63 Lund, Sweden. Electronic address: [email protected].
  • 2 RG Discovery AB, Medicon Village, SE-223 63 Lund, Sweden.
  • 3 Behavioral Pharma, 505 Coast Blvd South, Suite 212, La Jolla, CA 92037, United States.
  • 4 JL3Pharma LLC, 28 Cove Side Lane, Stonington, CT 06378, United States.
  • 5 ACADIA Pharmaceuticals Inc., 12830 El Camino Real #400, San Diego, California 92130, United States.
PMID: 42002053 DOI: 10.1016/j.bmcl.2026.130662
Abstract

A growing body of evidence indicates that inadequate symptom-relief from medical treatment with SSRIs may be enhanced by concomitant blockade of 5-HT2A. In a discovery program directed towards finding novel SSRIs suitable for combining with the 5-HT2A inverse agonist pimavanserin, we used a published in silico generated template as the starting point. Through a stepwise optimization of the template, we discovered that by first exchanging a benzyl substituent for a pyridyl-methyl substituent and then by introducing either a 5- or 6-membered aromatic heterocycle on the core benzene-ring, new compounds with improved metabolic stability and enhanced SERT-potency were obtained. The novel SSRIs had desirable ADME properties, decreased CYP-inhibition and comparable in vivo activity to commonly prescribed SSRIs. One compound (21d) selected for further characterization displayed high selectivity across 90 targets, and synergistic actions with pimavanserin in behavioral tests of anxiety and in microdialysis assessments of neurotransmitter release.

Keywords

5-HT; Benzylamine; Pimavanserin; SERT; SSRI; Structure-activity relationship (SAR).

Figures
Products