- New 1alpha,25-dihydroxy-19-norvitamin D3 compounds of high biological activity: synthesis and biological evaluation of 2-hydroxymethyl, 2-methyl, and 2-methylene analogues.
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New highly active isomers of the natural hormone 1alpha, 25-dihydroxyvitamin D3 possessing an exomethylene group at the 2-position were prepared in a convergent manner, starting with (-)-quinic acid and the corresponding (20R)- and (20S)-25-hydroxy Grundm
- Sicinski,Prahl,Smith,DeLuca
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- Potent antagonist for the vitamin D receptor: Vitamin D analogues with simple side chain structure
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We previously reported that 22S-butyl-25,26,27-trinor-1α,24- dihydroxyvitamin D3 2 was a potent VDR antagonist. The X-ray crystal structure of the ligand binding domain of VDR complexed with 2 indicated that this ligand induces an extra cavity within the ligand-binding pocket. The structure also showed that the ligand forms only poor hydrophobic interactions with helix 12 of the protein. Here, to study the effects of the induction of the extra cavity and of insufficient interactions with helix 12 on antagonism, we designed and synthesized a series of vitamin D3 analogues with or without a 22-alkyl substituent and evaluated their biological potency. We found that the 22-butyl analogues 3c and 5c act as full antagonists, the 22-ethyl analogues 3b, 4b, 5b, and 22-butyl analogue 4c act as partial agonists, and the others (3a, 4a, 5a, 6a, 6b, and 6c) act as full agonists for VDR. It is intriguing that 6c is a potent agonist for VDR, whereas its 26,27-dinor analogue 5c is a potent antagonist. Analogue 6c recruited coactivator SRC-1 well, but 5c did not. These results indicate that a combination of induction of the extra cavity and insufficient hydrophobic interactions with helix 12 is important for VDR antagonism in this class of ligands.
- Sakamaki, Yuta,Inaba, Yuka,Yoshimoto, Nobuko,Yamamoto, Keiko
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experimental part
p. 5813 - 5826
(2010/10/20)
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- 2-ALKYLIDENE-19-NOR-VITAMIN D DERIVATIVES FOR THE TREATMENT OF OSTEOGENESIS IMPERFECTA
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The present invention relates to the treatment of ostogenesis imperfecta by adminstering to a patient in need thereof a 2-alkylidene-19-nor-vitamin D derivative, optionally with a bisphosphonate. Particularly, the present invention relates to the treatmen
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Page/Page column 28; 29; 39; 40
(2010/11/08)
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- 2-Alkylidene-19-nor-vitamin D derivatives for the treatment of osteosarcoma
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The present invention relates to methods of treating osteosarcoma, the methods comprising administering to a patient in need thereof a 2-alkylidene-19-nor-vitamin D derivative. Particularly, the present invention relates to methods of treating osteosarcom
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Page/Page column 9
(2008/06/13)
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- 2-alkylidene-19-nor-vitamin D derivatives for the treatment of hypogonadism or andropause
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The present invention relates to methods of treating hypogonadism or andropause, the methods comprising administering to a patient in need thereof a 2-alkylidene-19-nor-vitamin D derivative. Particularly, the present invention relates to methods of treati
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Page/Page column 9
(2008/06/13)
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- 2-Alkylidene-19-nor-vitamin D derivatives for the treatment of frailty, muscle damage or sarcopenia
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The present invention relates to methods of treating frailty, muscle damage or sarcopenia, the methods comprising administering to a patient in need thereof a 2-alkylidene-19-nor-vitamin D derivative. Particularly, the present invention relates to methods
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Page/Page column 9
(2008/06/13)
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- 2-alkylidene-19-nor-vitamin D derivatives for enhancement of peak bone mass in adolescence
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The present invention relates to methods of enhancing peak bone mass in adolescence, the methods comprising administering to a patient in need thereof a 2-alkylidene-19-nor-vitamin D derivative. Particularly, the present invention relates to methods of en
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Page/Page column 9
(2008/06/13)
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- 2-aklylidene-19-nor-vitamin D derivatives for the treatment of anorexia or low bone mass in females exhibiting aggressive athletic behavior
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The present invention relates to methods of treating anorexia or low bone mass in females exhibiting aggressive athletic behavior, the methods comprising administering to a patient in need thereof a 2-alkylidene-19-nor-vitamin D derivative. Particularly,
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Page/Page column 9
(2008/06/13)
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- 2-alkylidene-19-nor-vitamin D derivatives for the treatment of osteopenia or male osteoporosis
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The present invention relates to methods of treating osteopenia or male osteoporosis, the methods comprising administering to a patient in need thereof a 2-alkylidene-19-nor-vitamin D derivative. Particularly, the present invention relates to methods of t
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Page/Page column 9
(2008/06/13)
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- Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and an estrogen
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The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and an estrogen, or a pharmaceutically acceptable salt
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Page/Page column 12
(2008/06/13)
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- Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and a bone morphogenetic protein
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The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivatives and a bone morphogenetic protein or active fragment or
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Page/Page column 12
(2010/02/11)
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- Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and parathyroid hormone
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The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and parathyroid hormone or an active fragment or varian
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Page/Page column 12
(2010/02/11)
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- Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and a bisphosphonate
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The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and a bisphosphonate. Particularly, the present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof 2-methylene-19-nor-20(S)-1α, 25-dihydroxyvitamin D3and a bisphosphonate.
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Page/Page column 13
(2010/02/11)
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- Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and a cyclooxgenase-2 inhibitor
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The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and a cyclooxgenase-2 inhibitor, or a pharmaceutically acceptable salt or prodrug thereof. Particularly, the present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof 2-methylene-19-nor-20(S)-10,25-dihydroxyvitamin D3 and a cyclooxgenase-2 inhibitor, or a pharmaceutically acceptable salt or prodrug thereof.
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Page/Page column 13
(2010/02/11)
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- Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and an EP2 or EP4 selective agonist
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The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and an EP2 or EP4 selective agonist or a pharmaceutically acceptable salt or prodrug thereof. Particularly, the present invention relates to pharmaceutical compositions and methods comprising administering to a patient in need thereof 2-methylene-19-nor-20(S)-1α,25-dihydroxyvitamin D3 and an EP2 or EP4 selective agonist or a pharmaceutically acceptable salt or prodrug thereof.
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Page/Page column 38
(2010/02/11)
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- Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and a growth hormone secretagogue
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The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and a growth hormone secretagogue or a pharmaceutically
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Page/Page column 16; 20; 21
(2010/02/11)
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- 2-ALKYLIDENE-19-NOR-VITAMIN D DERIVATIVES FOR THE TREATMENT OF RICKETS OR VITAMIN D DEFICIENCY
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The present invention relates to methods of treating osteopenia or male osteoporosis, the methods comprising administering to a patient in need thereof a 2- alkylidene-19-nor-vitamin D derivative. Particularly, the present invention relates to methods of
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Page/Page column 23
(2010/02/11)
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- 2-ALKYLIDENE-19-NOR-VIT AMIN D DERIVATIVES FOR THE TREATMENT OF HYPOCALCEMIC TETANY OR HYPROPARATHYROIDISM
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The present invention relates to methods of treating hypocalcemic tetany or hypoparathyroidism, the methods comprising administering to a patient in need thereof a 2-alkylidene-1 9-nor-vitamin D derivative. Particularly, the present invention relates to m
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Page/Page column 24
(2010/02/11)
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- Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and aromatase inhibitors
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The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and an aromatase inhibitor. Particularly, the present i
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Page/Page column 12; 13; 17
(2010/02/11)
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