The 2-Methoxymethyl Modification of p -Phenylenediamine Reduces the Sensitization Risk for Hairdressers to Hair Dyes-An Occupational Hand Exposure-Based Risk Assessment.

BACKGROUND: Allergic contact dermatitis involving the hands is a common occupational skin disease for hairdressers and the potent sensitizers p -phenylenediamine (PPD) and toluene-2,5-diamine (PTD) are associated with the development of occupational allergic contact dermatitis. OBJECTIVE: The aim of the study was to analyze whether the use of the moderate sensitizer 2-methoxymethyl-PPD (ME-PPD) in professional hair dyes is a suitable tool to reduce the occupational contact allergy risk for hairdressers. METHODS: Hand exposure of hairdressers (N = 11) to ME-PPD was analyzed under routine hair coloring conditions in commercial salons. By accounting for wet work and uneven hand exposure, the daily hand exposure was derived and compared with the occupational acceptable exposure level (AEL), that is, the sensitization induction threshold of ME-PPD adjusted for interindividual variability among workers. RESULTS: The daily hand exposure to ME-PPD was 1.6 µg/cm 2 , and the occupational AEL was 215 µg/cm 2 . The ratio of hand exposure to AEL was calculated as the margin of safety (MOS) against occupational sensitization. For ME-PPD, the MOS of 134 indicates a low likelihood of sensitization versus PPD and PTD with MOS values of 2.7 and 5.9, respectively. CONCLUSIONS: Our data predict that the use of ME-PPD in professional hair color products improves the protection of hairdressers against hair dye-related contact allergy versus the use of PPD and PTD.

Metabolism of the Selective Matrix Metalloproteinase-9 Inhibitor (R)-ND-336.

(R)-ND-336-designated as compound (R)-5-is a highly selective inhibitor of matrix metalloproteinase (MMP)-9 with efficacy in accelerating diabetic wound healing in murine models. (R)-ND-336 belongs to the class of thiirane inhibitors of MMPs and it is currently undergoing Investigation New Drug (IND)-enabling studies. We investigated the in vitro metabolism of (R)-ND-336 using S9 fractions obtained from mice, rats, dogs, minipigs, monkeys, and humans in order to select the rodent and nonrodent species for toxicology studies. Three metabolites were observed. One metabolite, M3, was observed across all species. Metabolite M2 was found in rats, monkeys, and humans. Metabolite M1 was observed only in rats. The identities of the metabolites were suggested by liquid chromatography/tandem mass spectroscopy (LC/MS-MS) analyses, which were authenticated by comparison to synthetic samples. Metabolites M2 and M3 arise from oxidative deamination of (R)-ND-336 by monoamine oxidase to give the arylaldehyde as a transient (and unobserved) intermediate. Reductive metabolism of this aldehyde gives the alcohol metabolite M2, while further oxidative metabolism of the aldehyde produces the carboxylate metabolite M3. A minor route of metabolism, seen only in rats, is N-acetylation of (R)-ND-336 to give the acetamide M1. The metabolism of (R)-ND-336 is distinctly different from that of the prototype member of this thiirane class ((±)-1, lacking the 4-aminomethyl aryl substituent) which is metabolized primarily by oxidation α to the sulfone to lead to a benzenesulfinate metabolite. All three metabolites are poorer MMP-9 inhibitors, compared to (R)-ND-336 (MMP-9, K i = 19 nM): M3, MMP-9 IC50 > 100 µM; M2, K i = 390 nM; and M1, IC50 > 100 µM). The rat and the minipig were selected as the rodent and nonrodent species, respectively, for toxicology studies.

Addressing cytotoxicity of 1,4-biphenyl amide derivatives: Discovery of new potent and selective 17ß-hydroxysteroid dehydrogenase type 2 inhibitors.

Four different classes of new 17ß-hydroxysteroid dehydrogenase type 2 (17ß-HSD2) inhibitors were synthesized, in order to lower the cytotoxicity exhibited by the lead compound A, via disrupting the linearity and the aromaticity of the biphenyl moiety. Compounds 3, 4, 7a and 8 displayed comparable or better inhibitory activity and selectivity, as well as a lower cytotoxic effect, compared to the reference compound A. The best compound 4 (IC50=160nM, selectivity factor=168, LD50≈25µM) turned out as new lead compound for inhibition of 17ß-HSD2.