title: Synthesis and biological evaluation of picolinamides as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).
abstract: Synthesis of a series of 6-substituted picolinamide derivatives and their inhibitory activities against 11β-hydroxysteroid dehydrogenase type 1 are described. Optimization of the initial hit compound, N-cyclohexyl-6-(piperidin-1-yl)picolinamide (1) from high throughput screening of in-house library resulted in the discovery of the highly potent and metabolically stable compound 25, which was efficacious in a mouse ex vivo pharmacodynamic model and reduced the fasting blood glucose and insulin levels in a HF/STZ mouse model after oral dosing.
authors.affiliation: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea; Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Je Ho
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors.forename: Shinae
authors.initials: S
authors.lastname: Kim
authors.affiliation: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Han
authors.affiliation: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Son
authors.affiliation: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors.forename: Young Ah
authors.initials: YA
authors.lastname: Shin
authors.affiliation: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors.forename: Jae-Sun
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: hgpk@snu.ac.kr.
authors.forename: Hyeung-Geun
authors.initials: HG
authors.lastname: Park
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056004:Molecular Dynamics Simulation; D010848:Picolinic Acids / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D010848:Picolinic Acids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C003142:picolinamide
keywords: 11β-HSD1 inhibitor; Diabetes; Metabolic stability; Metabolic syndrome; Picolinamide