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Derivatives of (phenylsulfonamido-methyl)nicotine and (phenylsulfonamido-methyl)thiazole as novel 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: synthesis and biological activities in vitro.

Zhang X, Zhou Y, Shen Y, Du LL, Chen JH, Leng Y, Shen JH - Acta Pharmacol. Sin. (2009)

Bottom Line: In dose-response studies, several compounds showed strong inhibitory activities with IC50 values at nanomolar or low nanomolar concentrations.Structure-activity relationships are also discussed with respect to molecular docking results.This study provides two promising new templates for 11beta-HSD1 inhibitors.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai 201203, China.

ABSTRACT

Aim: To design and synthese a novel class of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors, featuring the (phenylsulfonamido-methyl)pyridine and (phenylsulfonamido-methyl)thiazole framework.

Methods: Our initial lead 4-(phenylsulfonamido-methyl)benzamides were modified. Inhibition of human and mouse 11beta-HSD1 enzymatic activities by the new compounds was determined by a scintillation proximity assay (SPA) using microsomes containing 11beta-HSD1.

Results: Sixteen new compounds (6a-6h, 7a-7h) were designed, synthesized and bioassayed. In dose-response studies, several compounds showed strong inhibitory activities with IC50 values at nanomolar or low nanomolar concentrations. Structure-activity relationships are also discussed with respect to molecular docking results.

Conclusion: This study provides two promising new templates for 11beta-HSD1 inhibitors.

Show MeSH
Reagents and conditions: (a) і: Ti(OiPr)4; іі: NaBCNH3.
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fig7: Reagents and conditions: (a) і: Ti(OiPr)4; іі: NaBCNH3.

Mentions: (Phenylsulfonamido-methyl)pyridines and (phenylsulfonamido-methyl)thiazoles were prepared via the route shown in Scheme 1,2,3. Hydrogenation of the 6-cyanonicotinic acid (1) catalyzed by 10% Pd/C afforded 2 in excellent yields. Protection of the acid 2 using methyl ester by Fischer esterification with acidic methanol gave the key intermediate 3a, whereas 3b was prepared according to the four-step process described in the literature11. Sulfonylation of the amino ester 3a or 3b using 3-chlorobenzenesulfonyl chloride in the presence of triethylamine afforded intermediate 4. Hydrolysis of ester 4 in methanol using potassium hydroxide gave carboxylic acid 5 in high yields. Final products 6 and 7 were obtained by treatment of intermediate acid 5 with various amines using 1-hydroxybenzotriazole and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride as amide-coupling reagents. The non-commercially available variants of N-substituted cycloheptanamine 8 were prepared according to methodologies described in the literature12.


Derivatives of (phenylsulfonamido-methyl)nicotine and (phenylsulfonamido-methyl)thiazole as novel 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: synthesis and biological activities in vitro.

Zhang X, Zhou Y, Shen Y, Du LL, Chen JH, Leng Y, Shen JH - Acta Pharmacol. Sin. (2009)

Reagents and conditions: (a) і: Ti(OiPr)4; іі: NaBCNH3.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4007184&req=5

fig7: Reagents and conditions: (a) і: Ti(OiPr)4; іі: NaBCNH3.
Mentions: (Phenylsulfonamido-methyl)pyridines and (phenylsulfonamido-methyl)thiazoles were prepared via the route shown in Scheme 1,2,3. Hydrogenation of the 6-cyanonicotinic acid (1) catalyzed by 10% Pd/C afforded 2 in excellent yields. Protection of the acid 2 using methyl ester by Fischer esterification with acidic methanol gave the key intermediate 3a, whereas 3b was prepared according to the four-step process described in the literature11. Sulfonylation of the amino ester 3a or 3b using 3-chlorobenzenesulfonyl chloride in the presence of triethylamine afforded intermediate 4. Hydrolysis of ester 4 in methanol using potassium hydroxide gave carboxylic acid 5 in high yields. Final products 6 and 7 were obtained by treatment of intermediate acid 5 with various amines using 1-hydroxybenzotriazole and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride as amide-coupling reagents. The non-commercially available variants of N-substituted cycloheptanamine 8 were prepared according to methodologies described in the literature12.

Bottom Line: In dose-response studies, several compounds showed strong inhibitory activities with IC50 values at nanomolar or low nanomolar concentrations.Structure-activity relationships are also discussed with respect to molecular docking results.This study provides two promising new templates for 11beta-HSD1 inhibitors.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai 201203, China.

ABSTRACT

Aim: To design and synthese a novel class of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors, featuring the (phenylsulfonamido-methyl)pyridine and (phenylsulfonamido-methyl)thiazole framework.

Methods: Our initial lead 4-(phenylsulfonamido-methyl)benzamides were modified. Inhibition of human and mouse 11beta-HSD1 enzymatic activities by the new compounds was determined by a scintillation proximity assay (SPA) using microsomes containing 11beta-HSD1.

Results: Sixteen new compounds (6a-6h, 7a-7h) were designed, synthesized and bioassayed. In dose-response studies, several compounds showed strong inhibitory activities with IC50 values at nanomolar or low nanomolar concentrations. Structure-activity relationships are also discussed with respect to molecular docking results.

Conclusion: This study provides two promising new templates for 11beta-HSD1 inhibitors.

Show MeSH