N1-Benzoyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes: Development of 4-Chlorophenylcarboxa
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- 作者：Albane Kessler ; Hé ; lè ; ne Faure ; Christophe Petrel ; Didier Rognan ; Michè ; le Cé ; sario ; Martial Ruat ; Philippe Dauban ; Robert H. Dodd
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：August 24, 2006
- 年：2006
- 卷：49
- 期：17
- 页码：5119 - 5128
- 全文大小：305K
- 年卷期：v.49,no.17(August 24, 2006)
- ISSN：1520-4804
文摘
A structure-activity relationship (SAR) study was performed principally at the N1 position of N1-arylsulfonyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calciumsensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC50 of 5.4 ± 0.5 
M with respect to the inhibition ofcalcium-induced tritiated inositol phosphate ([3H]IP) accumulation in Chinese hamster ovarian (CHO) cellsexpressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led toa 6-fold increase in activity (7m, IC50 = 0.9 ± 0.2 M). Among the carboxamides synthesized, one of themost active compounds was the 4-chlorophenylcarboxamide (1S,2S,1'R)-7n (Calhex 231, IC50 = 0.33 ±0.02 M). The absolute configuration of (1S,2S,1'R)-7n was deduced from an X-ray crystallographic studyof one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1'R)-isomerscan be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR.Removal of the C-1' methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenylmoiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate[3H]IP accumulation in CHO cells expressing or not expressing the CaSR.
M with respect to the inhibition ofcalcium-induced tritiated inositol phosphate ([3H]IP) accumulation in Chinese hamster ovarian (CHO) cellsexpressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led toa 6-fold increase in activity (7m, IC50 = 0.9 ± 0.2 M). Among the carboxamides synthesized, one of themost active compounds was the 4-chlorophenylcarboxamide (1S,2S,1'R)-7n (Calhex 231, IC50 = 0.33 ±0.02 M). The absolute configuration of (1S,2S,1'R)-7n was deduced from an X-ray crystallographic studyof one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1'R)-isomerscan be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR.Removal of the C-1' methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenylmoiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate[3H]IP accumulation in CHO cells expressing or not expressing the CaSR.