Systematic Investigation of Dual-Target-Directed Ligands.

Multitarget-directed ligands (MTDLs) are compounds rationally designed to affect multiple targets, aiming for a better therapeutic profile. For over 20 years, MTDLs have garnered increasing attention, the idea being that their full potential would have been achieved, thanks to unprecedented target combinations and advanced medicinal chemistry strategies. This study presents a literature mining effort resulting in a data set of dual-target-directed ligands (DTDLs), the fundamental example of MTDLs. We used this data set to evaluate the rationale behind target selection and the chemical novelty of DTDLs targeting specific protein combinations. Our analysis focused on DTDL targets in terms of biological function, disease association, structure, and chemogenomic traits. We also compared DTDLs with single-target compounds. We found that well-known target pathology associations often guide DTDL design, leveraging existing chemical scaffolds and binding pocket similarities. These findings highlight the current state of the field and suggest substantial untapped potential for rational polypharmacology.

Galantamine-memantine hybrids for Alzheimer's disease: The influence of linker rigidity in biological activity and pharmacokinetic properties.

Neurodegenerative processes characterizing Alzheimer's disease (AD) are strictly related to the impairment of cholinergic and glutamatergic neurotransmitter systems which provoke synaptic loss. These experimental evidences still represent the foundation of the actual standard-of-care treatment for AD, albeit palliative, consisting on the coadministration of an acetylcholinesterase inhibitor and the NMDAR antagonist memantine. In looking for more effective treatments, we previously developed a series of galantamine-memantine hybrids where compound 1 (ARN14140) emerged with the best-balanced action toward the targets of interest paired to neuroprotective efficacy in a murine AD model. Unfortunately, it showed a suboptimal pharmacokinetic profile, which required intracerebroventricular administration for in vivo studies. In this work we designed and synthesized new hybrids with fewer rotatable bonds, which is related to higher brain exposure. Particularly, compound 2, bearing a double bond in the tether, ameliorated the biological profile of compound 1 in invitro studies, increasing cholinesterases inhibitory potencies and selective antagonism toward excitotoxic-related GluN1/2B NMDAR over beneficial GluN1/2A NMDAR. Furthermore, it showed increased plasma stability and comparable microsomal stability in vitro, paired with lower half-life and faster clearance in vivo. Remarkably, pharmacokinetic evaluations of compound 2 showed a promising increase in brain uptake in comparison to compound 1, representing the starting point for further chemical optimizations.