Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-04-10
2001-12-11
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06329357
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The current invention concerns a method for treatment of diseases caused by deficiency or overproduction of the vitamin D
3
metabolites. In particular, the current invention concerns therapeutic properties of 1&agr;,25-dihydroxyvitamin D
3
analogs which are selective agonists or antagonists for thegenomic and rapid nongenomic cellular responses affecting calcium and phosphorus absorption, resorption, mineralization, collagen maturation of bone and tubular reabsorption of phosphorus. The analogs of the invention are useful for treatment of bone diseases such as rickets, osteomalacia, osteoporosis, osteopenia, osteosclerosis, renal osteodystrophy; skin diseases, such as psoriasis; thyroid diseases, such as medullary carcinoma; brain diseases, such as Alzheimer's disease; parathyroid diseases, such as hyperparathyroidism, hypoparathyroidism, pseudoparathyroidism or secondary parathyroidism; liver and pancreas diseases, such as diabetes, cirrhosis, obstructive jaundice or drug-induced metabolism; intestine diseases, such as glucocorticoid antagonism, idiopathic hypercalcemia, malabsorption syndrome, steatorrhea, or tropical sprue; kidney disease, such as chronical renal disease, hypophosphatemic vitamin D-resistant rickets or vitamin D-dependent rickets; lung diseases, such as sarcoidosis; and for treatment of any other disease in which 1&agr;,25-dihydroxyvitamin D
3
or its pro-drugs are involved.
BACKGROUND ART AND RELATED DISCLOSURES
Vitamin D deficiency is known to lead to serious diseases, such as rickets in children and osteomalacia in adults. Vitamin D is a prohorirone of several active metabolites that behave as hormones. The most important of those metabolites is 1&agr;,25(OH)
2
-vitamin D
3.
Vitamin D
3
, also known as cholecalciferol or activated 7-dehydrocholesterol, is a secosteroidl responsible for a wide variety of biological responses in higher animals that include maintenance of calcium homeostasis, immunomodulation and selected cell differentiation.
Vitamin D
3
is formed in human skin by exposure to ultraviolet radiation from sun. In the skin, previtamin D
3
is synthesized photochemically from 7-dehydrocholesterol and is slowly isomerized to vitamin D
3
. Vitamin D
3
is converted in the liver into 25-hydroxyvitamin D
3
, the major circulating form of vitamin D
3
metabolite. In the kidney and in some other tissues, 25(OH)D
3
is further hydroxylated to a more metabolically active form known as 1&agr;,25-dihydroxyvitamin D
3
[1&agr;,25(OH)
2
D
3
] whose primary function is to increase calcium absorption from the intestine and promote normal bone formation and mineralization. Vitamin D and its derivatives are, therefore, important substances for calcium homeostasis in the human body.
1&agr;,25-dihydroxyvitamin D
3
[1&agr;,25(OH)
2
D
3
] is a steroid hormone derived from its parent vitamin D
3
by sequential hydroxylation in the liver and kidney. 1&agr;,25-dihydroxyvitamin D
3
is active in regulating mineral homeostasis, cell differentiation and proliferation. Many biological functions of 1&agr;,25(OH)
2
D
3
are mediated by its nuclear receptor [VDR
nuc
]. (
Endocr. Rev
., 16: 200-257 (1993)).
Vitamin D
3
, itself, is biologically inert. However, metabolism of vitamin D
3
to its metabolites, such as 1&agr;,25-dihydroxyvitamin D
3
[1&agr;,25(OH)
2
D
3
], results in the formation of biologically active compounds, which are responsible for two main types of biological responses, namely slow genomic and rapid nongenomic responses, involved in the vitamin D endocrine system function.
Slow genomic responses of 1&agr;,25(OH)
2
D
3
are generated by its interaction with nuclear receptors. The result of this interaction with nuclear receptors is the regulation of gene transcription (
Crit. Rev. Eukar. Gene Exp
., 2:65-109 (1992),
Annual Rev. Nutr
., 11:189-216 (1991),
Vitamin D: Gene Regulation, Structure
-
Function Analysis and Clinical Application
, Norman, A. W., Bouillon, R., and Thomasset, M., Eds., pp. 146-154, Walter de Gruyter, Berlin, Germany (1991)).
The nuclear receptor for 1&agr;,25(OH)
2
D
3
has been shown to be present in 30 different tissues and it belongs to the same super family of proteins that includes receptors for the steroid hormones, retinoic acid and thyroxine (
Crit. Rev. Eukar. Gene Exp
., 2:65-109 (1992),
FASEB J
., 2:3043-3053 (1988),
Endocr. Rev
., 3:331-366 (1982)).
In addition to the slow genomic responses, it has been recently discovered that 1&agr;,25(OH)
2
D
3
also mediates biological responses by a rapid nongenomic mechanism (
Vitamin D: Gene Regulation, Structure
-
Function Analysis and Clinical Application
, Norman, A. W., Bouillon, R., and Thomasset, M., Eds., pp. 146-154, Walter de Gruyter, Berlin, Germany (1991); and
Endocrinology
, 115:1476-1483 (1984). Recent discoveries by inventors and others have identified a series of rapid non-genomic effects of 1&agr;,25(OH)
2
D
3
that occur within seconds to minutes of exposure of cells to this steroid hormone (Rapid biological responses mediated by 1&agr;,25(OH)
2
-vitamin D
3
: A case study of transcaltachia, pp. 233-256, in
Vitamin D
, Feldman D. M., Glorieux, F. H., Pike, J. W., Eds., Academic Press, San Diego, Calif., (1997)). Evidence supporting the existence of a membrane receptor (VDR
mem
) for 1&agr;,25(OH)
2
D
3
which mediates the initiation of rapid responses in some cells is described in
J. Biol. Chem
., 264:20403-20406 (1989); and
J. Biol. Chem
., 269:23750-23756 (1994).
The rapid nongenomic responses of 1&agr;,25(OH)
2
D
3
have been demonstrated in a variety of systems which include transcaltachia, a rapid stimulation of intestinal calcium transport in the perfused chick intestine involving the opening of Ca
2+
channels, as described in
J. Biol. Chem
., 264:20265-20274 (1989); a rapid increase of intracellular Ca
2+
in human keratinocytes and skeletal muscle, as described in
Brit. J. Dermatol
., 124:230-235 (1991) and
Biochem T
., 281:349-352 (1992); rapid opening of voltage-gated Ca
2+
, as described in
Am. J. Physiol
., 265:F705:F711 (1993); chloride channels in the ROS 17/2.8 cell line, as described in
Biochem. Biophys. Res, Commun
., 225:551-556 (1996); rapid stimulation of sodium proton exchange in opossum kidney cells, as described in
Pflugers Arch
., 424:391-397 (1993)]; rapid action on phospholipid metabolism in several tissues and cell lines, as described in
Endocrinology
, 127:2738-2743 (1990) and
Am. J. Physiol
., 249:F117-F-123 (1985); rapid activation of protein kinase C in rat epithelium cells, as described in
J. Clin. Invest
., 85:1296-1303 (1990); and rapid activation of mitogen-activated protein kinase (MAP-kinase or p42
mapk
) in hepatic Ito cells and human keratinocytes, as described in
J. Biol. Chem
., 270:3642-3647 (1995) and
J. Invest. Dermatol
., 106:1212-1217 (1996).
Other rapid nongenomic cellular responses which are mediated by 1&agr;,25(OH)
2
D
3
include opening of voltage-gated Ca
2+
channels in rat osteosarcoma cells, as described in
Endocrinology
, 127:2253-2262 (1990) and
Am. J. Physiol
., 249:F117-F123 (1985), as well as other rapid effects in kidney, as described in
FEBS Lett
., 259:205-208 (1989), in liver, as described in
Endocrinology
, 127:2738-2743 (1990), in parathyroid cells, as described in
J. Biol. Chem
., 264:20403-20406 (1989) and in intestine, as described in
J. Bone Min. Res
., 7:457-463 (1992).
The rapid actions of 1&agr;,25(OH)
2
D
3
on the cell membrane are postulated to regulate cell biological functions and potentially to interact with other membrane-mediated kinase cascades or to engage in cross-talk with the cell nucleus to modify genomic responses of cell differentiation and proliferation as studied in the human leukemic NB4 cell line in
Endocrinology
, 139:457-465 (1998).
Enzyme MAP-kinase belongs to the family of serine/threonine protein kinases which can be activated by phosphorylation of a tyrosine residueinduced by mitogens or cell differentiating agents,
Norman Anthony W.
Okamura William H.
Badio Barbara P.
The Regents of the University of California
Verny Hana
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