Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD)

Authors: Bucki A, Marcinkowska M, Sniecikowska J, Zagorska A, Jamrozik M, Pawłowski M, GłuchLutwin M, Siwek A, Jakubczy M, Pytka K, Jastrzebska-Wiesek M, Partyka A, Mierzejewski P, Kołaczkowski M
Publication: Eur J Med Chem
Keywords: alzheimer's disease, Arylsulfonamide, BPSD, MTDL, Psychosis in dementia, Serotonin receptors
Software: ADMET Predictor®

Abstract

Patients suffering from dementia experience cognitive deficits and 90% of them show non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine, have been commonly used off-label to control the burdensome symptoms, though they cause serious side effects and further cognitive impairment. Therefore, the development of targeted therapy for BPSD, suitable for elderly patients, remains relevant.

A multitarget-directed ligand, acting on serotonin 5-HT2A and dopamine D2 receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT6Rs and 5-HT7Rs (potential pro-cognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic M3R and hERG channel is expected to reduce the risk of side effects. We obtained a series of stereoisomeric compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonamide fragment through pyrrolidin-1-yl-propyl linker.

N-[(3R)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-1-benzothiophene-2-sulfonamide showed a substantial affinity for the targets of interest (pKi = 8.32–9.35) and no significant interaction with the antitargets. Functional studies revealed its antagonist efficacy (pKB = 7.41–9.03). The lead compound showed a promising profile of antipsychotic-like activity in amphetamine- and MK-801-induced hyperlocomotion (MED = 2.5 mg/kg), antidepressant-like, as well as anxiolytic-like activity in mice (MED = 0.312 and 1.25 mg/kg in the forced swim and four-plate tests, respectively). Notably, the novel compound didn’t affect spontaneous locomotor activity, nor induced catalepsy or memory deficits (step-through passive avoidance test) in therapeutically relevant doses, which proved its benign safety profile. The overall pharmacological characteristics of the lead compound outperformed the reference drug quetiapine, making it a promising option for evaluation in the treatment of BPSD.