Discovery of novel inhibitors of human 11β-hydroxysteroid dehydrogenase type 1

Su, Xiaoyan; Vicker, Nigel; Trusselle, Melanie; Halem, Heather; Culler, Michael D.; Potter, Barry V. L.

doi:10.1016/j.mce.2008.08.006

Cited by 16 publications

(17 citation statements)

References 11 publications

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“…The 2-furanyl derivative ( 13 ) with an IC 50 at 249 nM has about the same potency as 3. 27 The 1-methyl-1 H -2-pyrrolyl compound ( 15 ) with an IC 50 of 114 nM exhibits a twofold higher potency than 3 . It is assumed that the pyrrolyl ring can form further interactions with the enzyme and/or alters the geometry of the molecule placing the adamantyl and/or the aromatic ring in a position to gain further binding in the active site.…”

Section: Resultsmentioning

confidence: 99%

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Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Halem²,

Thomas

et al. 2012

Bioorganic & Medicinal Chemistry

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Section: Resultsmentioning

confidence: 99%

“…Compounds 3 and 4 (Fig. 1) exhibit inhibition of 11β-HSD1 with IC 50 values in the 200-300 nM range when tested in the HEK-293 cell line transfected with the human 11β-HSD1 gene 27 . We performed further optimization on these hit compounds by varying the aromatic region and linker.…”

Section: Introductionmentioning

confidence: 99%

Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Halem²,

Thomas

et al. 2012

Bioorganic & Medicinal Chemistry

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“…A large variety of 11 β-HSD1 inhibitor classes have been synthesized [174][175][176], and some are under investigation by the pharmaceutical industry to treat type 2 diabetes and obesity [177]. The modulation of 11 β-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia, and obesity.…”

Section: Sodium-dependent Glucose Cotransporter-2 Inhibitorsmentioning

confidence: 99%

Diabetes Mellitus: New Challenges and Innovative Therapies

Sena¹,

Bento²,

Pereira³

et al. 2013

New Strategies to Advance Pre/Diabetes Care: Integrative Approach by PPPM

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Diabetes mellitus is a widespread disease prevalence and incidence of which increases worldwide. The introduction of insulin therapy represented a major breakthrough in type 1 diabetes; however, frequent hyper-and hypoglycemia seriously affects the quality of life of these patients. New therapeutic approaches, such as whole pancreas transplant or pancreatic islet transplant, stem cell, gene therapy and islets encapsulation are discussed in this review. Regarding type 2 diabetes, therapy has been based on drugs that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase inhibitors) or improve insulin action (thiazolidinediones). This review is also focused on the newer therapeutically approaches such as incretin-based therapies, bariatric surgery, stem cells and other emerging therapies that promise to further extend the options available. Gene-based therapies are among the most promising emerging alternatives to conventional treatments. Some of these therapies rely on genetic modification of non-differentiated cells to express pancreatic endocrine developmental factors, promoting differentiation of nonendocrine cells into β-cells, enabling synthesis and secretion of insulin in a glucose-regulated manner. Alternative therapies based on gene silencing using vector systems to deliver interference RNA to cells (i.e. against VEGF in diabetic retinopathy) are also a promising therapeutic option for the treatment of several diabetic complications. In conclusion, treatment of diabetes faces now a new era that is characterized by a variety of innovative therapeutic approaches that will improve quality-life and allow personalized therapyplanning in the near future.

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“…HEK-293 sejtekben az adamantil-karboxamid új, potenciálisan szelektív 11-β-HSD-1 enzimgátló szernek bizonyult [41].…”

Section: A 11-β-hsd-1 Szintetikus Gátlószerei Mint íGéretes Terápiásunclassified

Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

et al. 2013

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A glükokortikoidok szabályozzák a szénhidrát-és aminosav-anyagcserét, modulálják az immunrendszer működé-sét és a stresszre adott válaszreakciókat. Elégtelen, illetve fokozott szekréciójuk jellegzetes kórképeket okoz. A szervezet glükokortikoidhormon-ellátottsága mellett az utóbbi évtizedben előtérbe került az adott szövetekben loká-lisan képződő glükokortikoidok patofi ziológiai szerepének kutatása. A lokális glükokortikoidellátottság egyik kulcsenzime a sejtek endoplazmatikus reticulumában elhelyezkedő 11-β-hidroxi-szteroid-dehidrogenáz enzim 1-es és 2-es típusa, amelyek az inaktív kortizon és az aktív kortizol közötti kétirányú átalakulást katalizálják. Az 1-es tí-pusú enzim elsősorban a kortizon aktiválásában játszik szerepet és főként a májban, gonádokban, zsírszövetben, agyban és csontban a biológiailag aktív kortizol lokális képződéséért felelős. Az enzimet kódoló gén az 1-es kromoszómán található. A szerzők jelen munkájukban összefoglalják a 11-β-hidroxi-szteroid-dehidrogenáz enzim 1-es típusának működésével kapcsolatba hozható klinikai és (kór)élettani folyamatokat. Összefoglalójukban áttekintik az enzimaktivitás gátlásában szerepet játszó genetikai variánsokkal kapcsolatos legfontosabb ismereteket és az enzimaktivitást gátló vegyületekkel szerzett tapasztalatokat. Az eredmények összegzéséből kitűnik, hogy bár ismereteink sok területen még hiányosak, az 1-es típusú enzim működésének és/vagy termelődésének gyógyszeres befolyásolása ígéretes terápiás lehetőséget jelenthet elhízásban, csontritkulásban vagy akár cukorbetegségben szenvedő betegek kezelésében. Orv. Hetil., 2013, 154, 283-293. Kulcsszavak: kortizol, kortizon, szövetspecifi kus glükokortikoidhatás, 11-β-hidroxi-szteroid-dehidrogenáz 1-es típus Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disordersGlucocorticoids play an important role in the regulation of carbohydrate and amino acid metabolism, they modulate the function of the immune system, and contribute to stress response. Increased and decreased production of glucocorticoids causes specifi c diseases. In addition to systemic hypo-or hypercortisolism, alteration of local synthesis and metabolism of cortisol may result in tissue-specifi c hypo-or hypercortisolism. One of the key enzymes participating in the local synthesis and metabolism of cortisol is the 11β-hydroxysteroid dehydrogenase enzyme. Two isoforms, type 1 and type 2 enzymes are located in the endoplasmic reticulum and catalyze the interconversion of hormonally active cortisol and inactive cortisone. The type 1 enzyme mainly works as an activator, and it is responsible for the generation of cortisol from cortisone in liver, adipose tissue, brain and bone. The gene encoding this enzyme is located on chromosome 1. The authors review the physiological and pathophysiological processes related to the function of the type 1 11β-hydroxysteroid dehydrogenase enzyme. They summarize the potential signifi cance of polymorphic variants of the enzyme in clinical diseases as well as knowledge related to inhibitors of...

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Discovery of novel inhibitors of human 11β-hydroxysteroid dehydrogenase type 1

Cited by 16 publications

References 11 publications

Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Diabetes Mellitus: New Challenges and Innovative Therapies

Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

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