title: Synthesis and optimization of picolinamide derivatives as a novel class of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors.
abstract: The synthesis and structure-activity relationship of a series of 6-substituted picolinamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1 are described. The optimization of the left-hand side of lead compound 1 resulted in the discovery of the highly potent, selective, and orally available inhibitor 24, which demonstrated an excellent activity in a mouse ex vivo pharmacodynamic model. Moreover, compound 24 reduced the blood glucose and improved the lipid profiles in ob/ob mice after oral administration.
authors: 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: Je Ho
authors: JH
authors: Ryu
authors: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors: Shinae
authors: S
authors: Kim
authors: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors: Jung A
authors: JA
authors: Lee
authors: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors: Hye Young
authors: HY
authors: Han
authors: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors: Hyun Joo
authors: HJ
authors: Son
authors: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors: Hyun Jung
authors: HJ
authors: Lee
authors: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors: Yong Hyuk
authors: YH
authors: Kim
authors: Life Science R&D Center, SK Chemicals, 686 Sampyeong-dong, Bundang-gu, Seongnam-si 463-400, Republic of Korea.
authors: Jae-Sun
authors: JS
authors: Kim
authors: 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: Hyeung-Geun
authors: HG
authors: Park
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000284:Administration, Oral; D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002384:Catalysis; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010165:Palladium / Q000737:chemistry; D010848:Picolinic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D008055:Lipids; D010848:Picolinic Acids; D010165:Palladium; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C003142:picolinamide
keywords: 11β-HSD1 inhibitor; Diabetes; Hyperlipidemia; Metabolic syndrome; Picolinamide