New Improved cGMP Analogues to Target Rod Photoreceptor Degeneration

  • J Med Chem. 2024 May 23;67(10):8396-8405. doi: 10.1021/acs.jmedchem.4c00586.
Oswaldo Pérez  1  2 ,  Agnese Stanzani  3 ,  Li Huang  3 ,  Nicolaas Schipper  1 ,  Thorsteinn Loftsson  2 ,  Martin Bollmark  1 ,  Valeria Marigo  3
Affiliations
  • 1. Chemical Processes and Pharmaceutical Development Research Institutes of Sweden, Forskargatan 20 J, 15136 Södertälje, Sweden.
  • 2. Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, 107 Reykjavik, Iceland.
  • 3. Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy.
PMID: 38688030 DOI: 10.1021/acs.jmedchem.4c00586
Abstract

Retinitis pigmentosa (RP) is a form of retinal degeneration affecting a young population with an unmet medical need. Photoreceptor degeneration has been associated with increased guanosine 3',5'-cyclic monophosphate (cGMP), which reaches toxic levels for photoreceptors. Therefore, inhibitory cGMP analogues attract interest for RP treatments. Here we present the synthesis of dithio-CN03, a phosphorodithioate analogue of cGMP, prepared using the H-phosphonothioate route. Two crystal modifications were identified as a trihydrate and a tetrahydrofuran monosolvates. Dithio-CN03 featured a lower aqueous solubility than its RP-phosphorothioate counterpart CN03, a drug candidate, and this characteristic might be favorable for sustained-release formulations aimed at retinal delivery. Dithio-CN03 was tested in vitro for its neuroprotective effects in photoreceptor models of RP. The comparison of dithio-CN03 to CN03 and its diastereomer SP-CN03, and to their phosphate derivative oxo-CN03 identifies dithio-CN03 as the compound with the highest efficacy in neuroprotection and thus as a promising new candidate for the treatment of RP.

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