N-Benzoyl anthranilic acid derivatives as selective inhibitors of aldo–keto reductase AKR1C3

• Published in: Bioorganic & medicinal chemistry letters 2012-09, Vol.22 (18), p.5948-5951
• Main Authors: Sinreih, Maša, Sosič, Izidor, Beranič, Nataša, Turk, Samo, Adeniji, Adegoke O., Penning, Trevor M., Rižner, Tea Lanišnik, Gobec, Stanislav
• Format: Article
• Language: English
• Subjects: 3-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; 3-Hydroxysteroid Dehydrogenases - metabolism; AKR1C3 inhibitors; Aldo-Keto Reductase Family 1 Member C3; Anthranilic acid; Anticancer agents; Biological and medical sciences; biosynthesis; chemistry; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; enzymes; Humans; Hydroxyprostaglandin Dehydrogenases - antagonists & inhibitors; Hydroxyprostaglandin Dehydrogenases - metabolism; Indexing in process; inhibitory concentration 50; Medical sciences; Models, Molecular; Molecular Structure; new drugs; ortho-Aminobenzoates - chemical synthesis; ortho-Aminobenzoates - chemistry; ortho-Aminobenzoates - pharmacology; Pharmacology. Drug treatments; prostaglandins; Stereoisomerism; steroid hormones; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.07.062

Human aldo–keto reductases AKR1C1–AKR1C3 are involved in the biosynthesis and inactivation of steroid hormones and prostaglandins and thus represent attractive targets for the development of new drugs. We synthesized a series of N-benzoyl anthranilic acid derivatives and tested their inhibitory activity on AKR1C enzymes. Our data show that these derivatives inhibit AKR1C1–AKR1C3 isoforms with low micromolar potency. In addition, five selective inhibitors of AKR1C3 were identified. The most promising inhibitors were compounds 10 and 13, with IC50 values of 0.31μM and 0.35μM for AKR1C3, respectively.