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Intrinsic Property Forecast Index (iPFI) as a Rule of Thumb for Medicinal Chemist to Remove a Phototoxicity Liability. Jean-Francois Fournier, Claire Bouix-Peter, Denis Duvert, Anne-Pascale Luzy, and Gilles Ouvry J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b00075 • Publication Date (Web): 16 Mar 2018 Downloaded from http://pubs.acs.org on March 18, 2018
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Journal of Medicinal Chemistry
Intrinsic Property Forecast Index (iPFI) as a Rule of Thumb for Medicinal Chemist to Remove a Phototoxicity Liability. Jean-François Fournier,* Claire Bouix-Peter, Denis Duvert, Anne-Pascale Luzy, and Gilles Ouvry. Nestlé Skin Health R&D, 2400 Route des colles, BP 87, 06902 Sophia-Antipolis Cedex, France Phototoxicity, photoallergy, drug-induced photosensitivity, iPFI, PFI, Property Forecast Index, ChromLogD
ABSTRACT: Phototoxicity occurs when UV irradiation causes otherwise benign compounds to become irritant, sensitizers or even genotoxic. This toxicity is particularly a concern after topical application and in dermatological programs where skin irritation can be incompatible with the desired therapeutic outcome. This brief article establishes that the intrinsic Property Forecast Index (iPFI) can be used to evaluate the probability of a compound being phototoxic and gives medicinal chemists a practical tool to handle this liability.
INTRODUCTION Phototoxicity, photoallergy or drug-induced photosensitivity, hereby referenced as phototoxicity, occurs when UV irradiation, for example by the sun, causes otherwise benign compounds to become irritant or even toxic. This would typically occur if said compound absorbs light in the UV spectrum to reach an excited state. From there, a number of processes could occur (ROS generation, transfer of energy, drug decomposition…) to account for the difference in skin toxicity vs the non-UV irradiated compound.1 Many common drugs such as NSAID ketoprofen and antibiotic lomefloxacin are phototoxic,1 although sometimes only a fraction of the patient population develops symptoms. Novel candidate drugs must therefore be screened for phototoxicity. In particular in dermatology, skin irritation is often incompatible with the desired therapeutic effect (eg skin inflammation in acne or atopic dermatitis) and should be screened for early on during the discovery stage, especially if the route of administration is topical where skin concentration in the upper layers is high. However a better approach for a medicinal chemist would be to understand the physico-chemical basis of phototoxicity in order to design molecules with lower risk. Furthermore, whereas in silico models can help selecting the most promising candidates, they tend to be black-box models that offer little practical help in the design phase and have been elaborated from limited datasets.2 We therefore embarked on a systematic analysis of our early-phase phototoxicity results in an in-house test (~1000 results produced under identical conditions) vs descriptors easily understood and manipulated at the molecular level by medicinal chemists. METHODOLOGY
Photocytotoxicity potential was assessed in a keratinocytes NRU assay adapted from the 3T3 NRU assay described in OECD guideline 432. Cells were irradiated with daylight UV simulation at 6 J/cm2. Cell viability was determined after 24h exposure with chemicals and a phototoxicity irritation factor (PIF) value was determined by the ratio of LC50 value with and without UV. Chemicals were classified as follow: PIF
