Discovery of SAR184841, a potent and long-lasting inhibitor of 11β-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D
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References and notes (30)
- et al.
Proc. Natl. Acad. Sci. U.S.A.
(1997)et al.Science
(2001) - et al.
Mini-Rev. Med. Chem.
(2008)et al.Expert Opin. Investig. Drugs
(2010)et al.Curr. Top. Med. Chem.
(2011) - et al.
J. Pharmacol. Exp. Ther.
(2002) - Receptor binding assays performed by Cerep...
- et al.
Endocr. Rev.
(2004) - et al.
Expert Rev. Cardiovasc. Ther.
(2005)et al.Drug Discovery Today
(2007) - et al.
J. Med. Chem.
(2002)et al.Diabetologia
(2002)et al.Bioorg. Med. Chem. Lett.
(2006)et al.J. Med. Chem.
(2009)et al.PLoS ONE
(2012) - et al.
J. Clin. Endocrinol. Metab.
(2002)et al.J. Clin. Endocrinol. Metab.
(2004)et al.J. Clin. Endocrinol. Metab.
(2001) - et al.
Semin. Vasc. Med.
(2004)
J. Clin. Invest.
J. Med. Chem.
J. Pharmacol. Exp. Ther.
J. Org. Chem.
J. Med. Chem.
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Application of carbamyl in structural optimization
2020, Bioorganic ChemistryCitation Excerpt :Crystal structure of compound 31 with human 11β-HSD1 (PDB: 4HX5) was also investigated. It showed the carbamyl generated hydrogen bond with the oxygen atom of NADP(H) and another hydrogen bond with Thr124 mediated by one water molecule, which was responsible for the potent biological activity [92]. From hit compound 32 (Fig. 5) showing moderate activity on 11β-HSD1 (IC50 = 390 nM), Lee et al. replaced the cyclohexane to adamantyl fragment and designed several analogues.
Progress in 11β-HSD1 inhibitors for the treatment of metabolic diseases: A comprehensive guide to their chemical structure diversity in drug development
2020, European Journal of Medicinal ChemistryCitation Excerpt :However, the adamantyl group was thought to be a cause of metabolic liability [83]. To address this problem, additional hydrophilic groups such as an amide, carboxylic acid or hydroxyl group were commonly linked to optimize their physico-chemical properties [77]. Moreover, similar to the adamantyl moiety, hydrophobic groups substituted phenyl or cyclohexane moiety was also commonly observed in 11β-HSD1 inhibitors to form the hydrophobic interaction with 11β-HSD1 [83].
Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction
2017, European Journal of Medicinal ChemistryCitation Excerpt :Given that the 11β-HSD1 active site includes a hydrophobic pocket that can accommodate bulky lipophilic substituents, the introduction of a lipophilic group, such as adamantyl, has proven a successful strategy for the space filling of the cavity. Thus, several adamantyl-containing 11β-HSD1 inhibitors exhibit high affinity and potency and some of them (e.g. AZD8329 and ABT-384) have reached clinical trials (Fig. 1) [26–34]. Although the evaluation of alternative polycyclic hydrocarbons may offer further opportunities for optimizing the space filling of the hydrophobic cavity, the use of other polycyclic substituents featuring different size or shape has only been briefly scrutinized (e.g. AMG-221 and MK-0736) [35,36].
Novel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold
2015, Bioorganic and Medicinal Chemistry LettersSynthesis and optimization of picolinamide derivatives as a novel class of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors
2015, Bioorganic and Medicinal Chemistry LettersSynthesis and biological evaluation of picolinamides as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
2015, Bioorganic and Medicinal Chemistry Letters