Penta-substituted benzimidazoles as potent antagonists of the calcium-sensing receptor (CaSR-antagonists)

被引：9

作者：

Gerspacher, Marc ^{[1
]}

Altmann, Eva ^{[1
]}

Beerli, Rene ^{[1
]}

Buhl, Thomas ^{[1
]}

Endres, Ralf ^{[1
]}

Gamse, Rainer ^{[1
]}

Kameni-Tcheudji, Jacques ^{[1
]}

Kneissel, Michaela ^{[1
]}

Krawinkler, Karl Heinz ^{[1
]}

Missbach, Martin ^{[1
]}

Schmidt, Alfred ^{[1
]}

Seuwen, Klaus ^{[1
]}

Weiler, Sven ^{[1
]}

Widler, Leo ^{[1
]}

机构：

[1] Novartis Pharma AG, Novartis Inst BioMed Res, CH-4002 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 17期

关键词：

Calcium-sensing receptor (CaSR); Parathyroid hormone (PTH); Bone formation; Osteoporosis; CaSR-antagonist; Benzimidazoles; BONE;

D O I：

10.1016/j.bmcl.2010.07.016

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel benzimidazole derivatives has been designed via a scaffold morphing approach based on known calcilytics chemotypes. Subsequent lead optimisation led to the discovery of penta-substituted benzimidazoles that exhibit attractive in vitro and in vivo calcium-sensing receptor (CaSR) inhibitory profiles. In addition, synthesis and structure-activity relationship data are provided. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5161 / 5164

页数：4

共 18 条

[1] Anabolic therapy for osteoporosis [J].

Bilezikian, John P. .

WOMENS HEALTH, 2007, 3 (02) :243-253

[2]

Brown E. M., 2007, V45, P139

[3] METHYL FLUOROSULFONYLDIFLUOROACETATE - A NEW TRIFLUOROMETHYLATING AGENT [J].

CHEN, QY ;

WU, SW .

JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1989, (11) :705-706

[4] Potential new drug targets for osteoporosis [J].

Deal, Chad .

NATURE CLINICAL PRACTICE RHEUMATOLOGY, 2009, 5 (01) :20-27

[5] The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats [J].

Dobnig, H ;

Turner, RT .

ENDOCRINOLOGY, 1997, 138 (11) :4607-4612

[6] Anabolic and catabolic bone effects of human parathyroid hormone (1-34) are predicted by duration of hormone exposure [J].

Frolik, CA ;

Black, EC ;

Cain, RL ;

Satterwhite, JH ;

Brown-Augsburger, PL ;

Sato, M ;

Hock, JM .

BONE, 2003, 33 (03) :372-379

[7] Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures [J].

Gallagher, JC ;

Genant, HK ;

Crans, GG ;

Vargas, SJ ;

Krege, JH .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2005, 90 (03) :1583-1587

[8] Parathyroid hormone update [J].

Hamann, Kendal L. ;

Lane, Nancy E. .

RHEUMATIC DISEASE CLINICS OF NORTH AMERICA, 2006, 32 (04) :703-+

[9] Allosteric modulation of the calcium-sensing receptor [J].

Jensen, Anders A. ;

Brauner-Osborne, Hans .

CURRENT NEUROPHARMACOLOGY, 2007, 5 (03) :180-186

[10] A reference standard for the description of osteoporosis [J].

Kanis, John A. ;

McCloskey, Eugene V. ;

Johansson, Helena ;

Oden, Anders ;

Melton, L. Joseph, III ;

Khaltaev, Nikolai .

BONE, 2008, 42 (03) :467-475

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