title: Synthesis and biological evaluation of Esaprazole analogues showing σ1 binding and neuroprotective properties in vitro.
abstract: Esaprazole, a molecule previously acknowledged to protect against stomach and intestinal ulcers was surprisingly discovered to have neuroprotective activities and σ1 binding in vitro. A highly diverse set of Esaprazole analogues 2-5 was prepared in order to increase blood-brain barrier penetration. The analogues showed a structure-activity relationship at the σ1 receptor closely matching already published pharmacophores. Many of the analogues were shown to have neuroprotective properties in two assays using primary cultures of cortical neurons exposed to glutamate and hydrogen peroxide. However, no apparent SAR for these two assays could be developed. Metabolic stability of the analogues were also investigated and the structure of R(1) had a significant bearing on the ADME properties of the compound resulting in two series of compounds. Compounds in which R(1) was a H or acyl group had good metabolic stability in RLM but poor BBB penetration, whereas compounds where R(1) was a cyclo- or bicyclo-alkyl group had poor metabolic stability but good BBB penetration.
authors.affiliation: Nensius Research A/S, Symbion Science Park, Fruebjergvej 3, DK-2100 Copenhagen, Denmark. nk.nensius@gmail.com
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Kelly
authors.forename: Anja
authors.initials: A
authors.lastname: Wellejus
authors.forename: Heidi
authors.initials: H
authors.lastname: Elbrønd-Bek
authors.forename: Morten Sloth
authors.initials: MS
authors.lastname: Weidner
authors.forename: Signe Humle
authors.initials: SH
authors.lastname: Jørgensen
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002199:Capillary Permeability; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004355:Drug Stability; D018698:Glutamic Acid / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061251:Primary Cell Culture; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000897:Anti-Ulcer Agents; D018696:Neuroprotective Agents; D010879:Piperazines; D017480:Receptors, sigma; C042123:esaprazole; D018698:Glutamic Acid; D006861:Hydrogen Peroxide