title: Discovery of pyridyl sulfonamide 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors for the treatment of metabolic disorders.
abstract: A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11β-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability.
authors.affiliation: Department of Chemistry, Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Yoon
authors.affiliation: Department of Chemistry, Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA.
authors.forename: Shung C
authors.initials: SC
authors.lastname: Wu
authors.affiliation: Lead Evaluation, Research and Development, Bristol-Myers Squibb, PO Box 5400-5400, Princeton, NJ 08543, USA.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.affiliation: Lead Evaluation, Research and Development, Bristol-Myers Squibb, PO Box 5400-5400, Princeton, NJ 08543, USA.
authors.forename: Rajasree
authors.initials: R
authors.lastname: Golla
authors.affiliation: CADD, Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA.
authors.forename: Akbar
authors.initials: A
authors.lastname: Nayeem
authors.affiliation: PCO Discovery Pharmaceutics, Research and Development, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Everlof
authors.affiliation: Department of Biology, Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Gordon
authors.affiliation: Department of Chemistry, Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA.
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
authors.affiliation: Department of Chemistry, Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008659:Metabolic Diseases / Q000188:drug therapy*; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2
keywords: 11-Beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1); Enzyme inhibitor; Pyridyl sulfonamide; Type-2 diabetes