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Identification and characterization of sebaceous gland atrophy-sparing DGAT1 inhibitors.

Muise ES, Zhu Y, Verras A, Karanam BV, Gorski J, Weingarth D, Lin HV, Hwa J, Thompson JR, Hu G, Liu J, He S, DeVita RJ, Shen DM, Pinto S - PLoS ONE (2014)

Bottom Line: DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects.One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme.In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.

View Article: PubMed Central - PubMed

Affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.

ABSTRACT
Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.

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Histopathology versus lipophilicity.Calculated logD (clogD, A) or measured logD (mlogD, B) versus observed skin adverse effects. Data is jittered on the y-axis to improve visualization.
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pone-0088908-g003: Histopathology versus lipophilicity.Calculated logD (clogD, A) or measured logD (mlogD, B) versus observed skin adverse effects. Data is jittered on the y-axis to improve visualization.

Mentions: To gain a better understanding of the chemical physical properties of DGAT1 inhibitors as it relates to skin AEs, we evaluated lipophlicity (Log D) of these compounds which can be either measured by HPLC (mlogD) or calculated using the ACD software (clogD). Distribution into skin can be understood as a partitioning equilibrium dependent on compound properties. As listed in Table 1, 7 out of 22 compounds tested (Cpd2, 3, 5, 6, 12, 15, 22) were found to induce either “minimal to mild” or “moderate to marked” skin sebaceous gland atrophy after 14 days of treatment. Compounds with sufficient potency against the mouse enzyme (mDGAT1 IC50 nM) only show skin toxicity as measured by histopathology at sufficient exposure levels in the skin (Table 1). Interestingly, we find that compounds with skin effects can be distinguished from compounds without observable skin effects by plotting lipophilicity (clogD) against the observed histopathology (Figure 3). Compounds which show significant or minimal adverse effects in skin generally have a predicted clogD of greater than 1, while compounds with no observable effects all have a predicted clogD of less than 0.7.


Identification and characterization of sebaceous gland atrophy-sparing DGAT1 inhibitors.

Muise ES, Zhu Y, Verras A, Karanam BV, Gorski J, Weingarth D, Lin HV, Hwa J, Thompson JR, Hu G, Liu J, He S, DeVita RJ, Shen DM, Pinto S - PLoS ONE (2014)

Histopathology versus lipophilicity.Calculated logD (clogD, A) or measured logD (mlogD, B) versus observed skin adverse effects. Data is jittered on the y-axis to improve visualization.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928314&req=5

pone-0088908-g003: Histopathology versus lipophilicity.Calculated logD (clogD, A) or measured logD (mlogD, B) versus observed skin adverse effects. Data is jittered on the y-axis to improve visualization.
Mentions: To gain a better understanding of the chemical physical properties of DGAT1 inhibitors as it relates to skin AEs, we evaluated lipophlicity (Log D) of these compounds which can be either measured by HPLC (mlogD) or calculated using the ACD software (clogD). Distribution into skin can be understood as a partitioning equilibrium dependent on compound properties. As listed in Table 1, 7 out of 22 compounds tested (Cpd2, 3, 5, 6, 12, 15, 22) were found to induce either “minimal to mild” or “moderate to marked” skin sebaceous gland atrophy after 14 days of treatment. Compounds with sufficient potency against the mouse enzyme (mDGAT1 IC50 nM) only show skin toxicity as measured by histopathology at sufficient exposure levels in the skin (Table 1). Interestingly, we find that compounds with skin effects can be distinguished from compounds without observable skin effects by plotting lipophilicity (clogD) against the observed histopathology (Figure 3). Compounds which show significant or minimal adverse effects in skin generally have a predicted clogD of greater than 1, while compounds with no observable effects all have a predicted clogD of less than 0.7.

Bottom Line: DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects.One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme.In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.

View Article: PubMed Central - PubMed

Affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.

ABSTRACT
Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.

Show MeSH
Related in: MedlinePlus