Dataset Information

Structure Activity Relationships of ?v Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents.

ABSTRACT: Antagonism of ?v?6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an ?v?3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved ?v?6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan ?v antagonists having ca. 100 nM potency against ?v?3, ?v?5, ?v?6, and ?v?8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for ?v?3 and ?v?5.

SUBMITTER: Adams J

PROVIDER: S-EPMC4233353 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Structure Activity Relationships of αv Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents.

Adams James J Anderson Edward C EC Blackham Emma E EE Chiu Yin Wa Ryan YW Clarke Thomas T Eccles Natasha N Gill Luke A LA Haye Joshua J JJ Haywood Harvey T HT Hoenig Christian R CR Kausas Marius M Le Joelle J Russell Hannah L HL Smedley Christopher C Tipping William J WJ Tongue Tom T Wood Charlotte C CC Yeung Jason J Rowedder James E JE Fray M Jonathan MJ McInally Thomas T Macdonald Simon J F SJ

ACS medicinal chemistry letters 20140919 11

Antagonism of αvβ6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an αvβ3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved αvβ6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan ...[more]

PMID: 25408832

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Project description:Introdution and Aims: The myokine irisin is critical to modulating adipocytes thermogenesis and influence whole-body metabolism. However, whether there is difference in the effects of irisin on adipocytes derived from different depots remains unknown, and the receptor of irisin on adipocytes is still unclear. In this study, we determine the browning effect of irisin on adipocytes of subcutaneous and visceral human adipose tissue and explore the possibility that integrin αV was the receptor of irisin on human adipocytes.MethodsHuman adipose-derived stem cells were isolated from human subcutaneous and visceral white adipose tissues and induced to differentiate into mature adipocytes, and the expression of UCP1 and thermogenic genes in mature adipocytes were examined with or without irisin treatment and compared between groups of different adiposity and different spots. Immunoprecipitation analysis was used to detect the interaction between irisin and integrin αV on adipocytes, and the protein expression of integrin αV in adipocytes was also compared between groups of different adiposity and anatomic position.ResultsIrisin treatment could increase the expression level of beige adipocyte marker protein UCP1 and specific thermogenic genes in mature adipocytes derived from subcutaneous white adipose tissue but not in visceral adipose tissue. The results of immunoprecipitation showed that irisin could be attached to integrin αV on mature adipocytes, and there was no significant difference in the gene and protein expression of integrin αV in adipocytes, either derived from subcutaneous and visceral adipose tissue, or derived from obese and normal-weight individuals.ConclusionThe results of the present study indicated that irisin contributed to the transformation of mature white adipocytes to beige adipocytes in human subcutaneous adipose tissue but not in visceral adipose tissue. Integrin αV may mediate the browning effects of irisin on human mature adipocytes, which could provide the potential therapeutic targets for obesity and metabolic syndrome by promoting human brown adipose tissue activity.

Dataset Information

Structure Activity Relationships of ?v Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents.

Publications

Structure Activity Relationships of αv Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents.

Similar Datasets

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