: 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.

New Improved cGMP Analogues to Target Rod Photoreceptor Degeneration / Pérez, O.; Stanzani, A.; Huang, L.; Schipper, N.; Loftsson, T.; Bollmark, M.; Marigo, V.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - (2024), pp. 1-12. [10.1021/acs.jmedchem.4c00586]

New Improved cGMP Analogues to Target Rod Photoreceptor Degeneration

Stanzani A.
Methodology
;
Huang L.
Formal Analysis
;
Marigo V.
Conceptualization
2024

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.
2024
1
12
New Improved cGMP Analogues to Target Rod Photoreceptor Degeneration / Pérez, O.; Stanzani, A.; Huang, L.; Schipper, N.; Loftsson, T.; Bollmark, M.; Marigo, V.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - (2024), pp. 1-12. [10.1021/acs.jmedchem.4c00586]
Pérez, O.; Stanzani, A.; Huang, L.; Schipper, N.; Loftsson, T.; Bollmark, M.; Marigo, V.
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