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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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Related in: MedlinePlus

Representative compound structures from three chemical compound series as shown in Table 1.
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pone-0088908-g001: Representative compound structures from three chemical compound series as shown in Table 1.

Mentions: Several DGAT1 inhibitors across different structural classes were tested for their effect on skin morphology after chronic treatment in mice (Figure 1 and Table 1). Compounds were separated into structural classes and assigned to groups A to E. Representative structures from groups A, B, and C are shown in Figure 1 (structures of compounds from groups D and E will be the subject of future reports). After 14 days of oral dosing several compounds either induced sebaceous gland atrophy in the skin or showed no response. As shown in Figure 2, the sebaceous glands in the skin of mice treated with either vehicle or Cpd1 (3 mg/kg, 14 days) appeared normal while the skin of mice treated with Cpd2 (30 mg/kg, 14 days) had moderate to marked atrophic sebaceous glands on the dorsal surface, which were characterized by an overall decreased amount and size of sebaceous gland acini. Skin of mice treated with Cpd3 (30 mg/kg, 14 days) showed minimal to mild effects. The affected sebaceous gland units had fewer acinar cells and/or cells with decreased amount of cytoplasmic vacuolation. Frequently the sebaceous gland acini had consolidated, eosinophilic cytoplasm and pyknotic nuclei. No other histomorphologic changes were observed in these skin sections. Compound plasma exposures (Plasma µM) did not correlate with skin AEs (Scoring) or with skin exposure (Skin/Plasma Ratio; Table 1). However, skin exposures as it related to IC50 did correlate with skin AEs (Skin/IC50). The effects of the compounds were similar on ventral skin (Figure S1). Of note, longer exposure of Cpd1, which did not cause sebaceous gland atrophy at 14 days, in rats at up to 300 mg/kg for 4 weeks had no adverse effects in skin (data not shown). Additional studies will be required to study the effects of these compounds in skin after longer-term exposure.


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)

Representative compound structures from three chemical compound series as shown in Table 1.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0088908-g001: Representative compound structures from three chemical compound series as shown in Table 1.
Mentions: Several DGAT1 inhibitors across different structural classes were tested for their effect on skin morphology after chronic treatment in mice (Figure 1 and Table 1). Compounds were separated into structural classes and assigned to groups A to E. Representative structures from groups A, B, and C are shown in Figure 1 (structures of compounds from groups D and E will be the subject of future reports). After 14 days of oral dosing several compounds either induced sebaceous gland atrophy in the skin or showed no response. As shown in Figure 2, the sebaceous glands in the skin of mice treated with either vehicle or Cpd1 (3 mg/kg, 14 days) appeared normal while the skin of mice treated with Cpd2 (30 mg/kg, 14 days) had moderate to marked atrophic sebaceous glands on the dorsal surface, which were characterized by an overall decreased amount and size of sebaceous gland acini. Skin of mice treated with Cpd3 (30 mg/kg, 14 days) showed minimal to mild effects. The affected sebaceous gland units had fewer acinar cells and/or cells with decreased amount of cytoplasmic vacuolation. Frequently the sebaceous gland acini had consolidated, eosinophilic cytoplasm and pyknotic nuclei. No other histomorphologic changes were observed in these skin sections. Compound plasma exposures (Plasma µM) did not correlate with skin AEs (Scoring) or with skin exposure (Skin/Plasma Ratio; Table 1). However, skin exposures as it related to IC50 did correlate with skin AEs (Skin/IC50). The effects of the compounds were similar on ventral skin (Figure S1). Of note, longer exposure of Cpd1, which did not cause sebaceous gland atrophy at 14 days, in rats at up to 300 mg/kg for 4 weeks had no adverse effects in skin (data not shown). Additional studies will be required to study the effects of these compounds in skin after longer-term exposure.

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