Improving the solubility of pseudo-hydrophobic Alzheimer's Disease medicinal chemicals through co-crystal formulation

A Tse; I Janilkarn-Urena; J Lin; X Chang; C Efthymiou; A Idrissova; M Zhang; C K Williams; S Magaki; H V Vinters; D L Davies; T Gonen; H J Gukasyan; P M Seidler

doi:10.1101/2023.04.25.538327

Improving the solubility of pseudo-hydrophobic Alzheimer's Disease medicinal chemicals through co-crystal formulation

bioRxiv [Preprint]. 2023 Apr 28:2023.04.25.538327. doi: 10.1101/2023.04.25.538327.

Authors

A Tse^{1

2}, I Janilkarn-Urena^{1

2}, J Lin^{3

4

5

2}, X Chang¹, C Efthymiou¹, A Idrissova¹, M Zhang¹, C K Williams⁶, S Magaki⁶, H V Vinters^{6

5}, D L Davies⁷, T Gonen^{3

4

8}, H J Gukasyan¹, P M Seidler¹

Affiliations

¹ Department of Pharmacology and Pharmaceutical Sciences, University of Southern California Mann School of Pharmacy and Pharmaceutical Sciences, 1985 Zonal Ave, Los Angeles, CA 90089-9121, USA.
² Authors contributed equally to experimental work.
³ Department of Biological Chemistry, University of California Los Angeles, 615 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
⁴ Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, California 90095.
⁶ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, California 90095.
⁷ Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA 90089, USA.
⁸ Department of Physiology, University of California Los Angeles, 615 Charles E. Young Drive South, Los Angeles, CA 90095, USA.

Abstract

Natural products are ligands and potential inhibitors of Alzheimer's disease (AD) tau. Dihydromyricetin (DHM) is a CNS active natural product. Despite having signature polyphenolic character, DHM is ostensibly hydrophobic owing to intermolecular hydrogen bonds that shield hydrophilic phenols. Our research shows DHM becomes ionized at near-neutral pH allowing formulation of salts with transformed solubility. The MicroED co-crystal structure with trolamine reveals DHM salts as metastable solids with unlocked hydrogen bonding and a thermodynamic bent to solubilize in water. All salt formulations show better inhibitory activity against AD tau than the non-salt form, with efficacies correlating to enhanced solubilities. These results underscore the role of structural chemistry in guiding selection of solubilizing agents for chemical formulation. We propose DHM salts are appropriate formulations for research as dietary supplements to promote healthy aging by combating protein misfolding. Additionally, DHM is a suitable lead for medicinal chemistry and possible development of CNS pharmaceuticals.

Publication types

Preprint