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Compound
CDRI-99/373
(A new antiosteoporosis / anti-resorptive
agent )
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| CDRI-99/373 |
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| Osteoporosis
accompanying menopause and other estrogen
deficiency states such as ovarian
dysgenesis/dysfunction, hyperprolactinemia,
ovariectomy due to ovarian cancer,
estrogen receptor abnormality in target
tissues, aromatase deficiency, exogenous
treatment with GnRH agonist/antagonist
or aromatase inhibitors represents
a major cause of morbidity and mortality
in women the world-over. This is due
to estrogen-deficiency induced increased
generation and function of bone resorbing
cells or osteoclasts, which perforate
bone trabeculae and reduce their strength
resulting in increased fracture risk.
Hormone/estrogen replacement therapy,
though highly effective in preventing
bone loss following menopause, is
known to be associated with increased
risk of endometrial hyperplasia and
carcinoma, cancer breast and thromboembolic
diseases, in addition to other estrogen-related
health hazards. Pertinently, raloxifene,
a Selective Estrogen Receptor Modulator,
reported to mimic effects of estrogen
in bone and cardiovascular system
and exhibit estrogen antagonistic
effect in endometrial tissue, has
recently been reported to increase
incidence of hot flashes, deep vein
thrombosis, pulmonary embolism and
leg cramps similar to that associated
with use of Hormone Replacement Therapy.
It also induces weak, but significant,
uterotrophic response with significant
increase in uterine dry weight and
height, mitotic activity, vacuolization
and degeneration of uterine luminal
epithelial cells and number of endometrial
glands in immature and ovariectomized
rats and a potent estrogenic effect
on hypothalamo-pituitary-ovarian axis.
Of the other marketed anti-resorbing
agents, bisphosphonates are associated
with upper gastrointestinal disturbances,
esophagitis and oesophageal ulcers
and erosions, while calcitonin has
been reported to cause nasal dryness,
soreness, irritation and epistaxis.
Efforts are, therefore, being made
to develop agents that can prevent
bone loss associated with estrogen-deficiency,
but lack proliferative effects of
estrogen on the endometrium and breast
and are free from other health hazards.
Compound CDRI-99/373 is a novel anti-resorbing
agent. Its antiosteoporosis and related
activities are summarized below: |
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| Antiresorptive
activity in vitro and in vivo |
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- It inhibits PTH-induced resorption of
45Ca from chick fetal femora with T/C
ratio of 0.77, 0.60 and 0.44 at 25, 50
and 100 ?M concentrations, in comparison
to T/C of 0.66 in case of Raloxifene (100
?M).
- It inhibits bone marrow derived M-CSF
and RANKL induced osteoclastogenesis at
0.01 and 1 µM conc. in vitro. Raloxifene
at these concentrations does not show
any such activity.
- Like raloxifene, it does not induce
apoptosis of mature osteoclasts in vitro
at 1 ?M concentration.
- It decreases the expression of calcitonin
receptors, the functional marker of activated
osteoclasts, and also disrupted F-actin
ring in vitro.
- It inhibits expression of c-src gene
responsible for polarisation of osteoclasts
in vitro.
- It does not show any cytotoxicity in
concentration range of 0.62-20 ?g/ml against
certain cancer (Miapaca2, Pa1, HBL100,
HT29) and non-cancer (Balbc3T3) cell lines
in vitro.
- It prevents ovariectomy-induced decrease
in BMD in femur neck and proximal tibia
bones, known to contain primarily trabecular
bone, which is susceptible to loss in
estrogen deficiency states, in retired
breeder as well as adult female rats to
attain levels almost comparable to that
of sham-operated vehicle treated intact
control group.
- It inhibits ovariectomy-induced down-regulation
of TGF?-3 expression in lumbar vertebrae
of retired breeder rats; the effect appears
better than that after raloxifene.
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| Synthesis
and Stability |
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- It is a synthetic compound requiring
single step, convenient and economic synthesis
with an overall yield of about 60%.
- HPLC-UV method with linearity range
of 5-500 ng/ml and >85% recovery from
rat serum, urine and faeces with acceptable
accuracy and precision has been developed
and validated.
- It is stable under accelerated conditions
of temperature and humidity, when exposed
to direct sunlight or to UV irradiation
in solid state and in aqueous solutions
and in acidic and basic pH in simulated
gastric and intestinal fluids.
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| Regulatory
pharmacology, toxicology and pharmacokinetics |
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- It possesses high therapeutic window
with MLD/MTD of >2150 mg/kg and is
devoid of any major CVS and CNS effects
in mice and rats.
- It has been found safe in single, 10-day
and 28-day toxicity studies in rats and
its NOEL (No-Observed-Effect-Level) dose
has been suggested to be 0.75 g/kg, po.
- It exhibits moderate binding (average:
60.5±3.2%) to serum proteins in
vitro and the binding appears to be independent
of compound concentration in the serum.
- In rats treated with single (10 mg/kg,
po) dose, it was monitored in serum up
to 4 h with multiple Cmax (17.5, 10.9
and 13.1 ng/ml at 0.5, 1 and 3 h, respectively)
indicating enterohepatic recirculation.
The AUC and MRT were found to be 39.11
ng.h/ml and 1.8 h, respectively. Significant
levels of two metabolites have been detected
in serum of these rats at 30 min onwards
indicating its rapid metabolism. Both
the metabolites have been identified.
- In in vitro metabolic studies using
liver S-9 fraction, it was metabolized
fast and two metabolites were detected
and identified. These were identical to
the metabolites identified in in vivo
studies.
- It has been monitored in faeces up to
120 h post dose. Maximum amount of the
dose was excreted by 24 h. Cumulative
amount of the unchanged compound excreted
up to 72 h in faeces was 10.02±4.94%.
Urine samples collected up to 120 h post
dose show absence of either the parent
compound or any additional chromatographic
(metabolite) peak.
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| Relative
binding affinity and estrogenicity profile |
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- It does not show any competitive binding
to purified human estrogen receptor isoforms
alpha and beta or to rat uterine cytosol
or MCF-7 cell lysate. Raloxifene, in comparison,
exhibits RBA of 69% and 16% (% of estradiol-17?)
to human ER? and ER?, respectively.
- It is devoid of estrogen agonistic activity
at the uterine/endometrial level in ovariectomized
immature, retired breeder and adult female
rats as evidenced bylack of effect on
uterine weight, total uterine and endometrial
area and luminal epithelial cell height.
It also does not induce transcription
of estrogen receptors in MCF-7 cells in
vitro or induce uterine progesterone receptor
expression in ovariectomized immature
rats. Raloxifene, in comparison, induced
significant uterine weight gain as well
as increase in endometrial thickness and
luminal epithelial cell height. Compound
99/373 should, therefore, be devoid of
ERT/HRT/raloxifene related health hazards.
- In ovariectomized immature rat bioassay,
oral administration of this compound at
10 mg/kg dose for 3 consecutive days induced
32% inhibition in ethynylestradiol-induced
- uterine weight gain, in comparison to
37% inhibition observed at 0.25 mg/kg
dose of raloxifene. It also inhibited
estradiol induced transcription of estrogen
receptors in MCF-7 cells in vitro at 10-12
to 10-6 M conc. In case of raloxifene,
the inhibition was observed only at higher
concentrations of 10-9 to 10-6 M.
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| Value
addition |
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- In ongoing studies in female rats, it
causes regression of DMBA-induced mammary
tumor. The activity is comparable to that
of tamoxifen.
- Preliminary studies indicate inhibition
in ovariectomy-induced increase in serum
total cholesterol concentration in adult
as well as retired breeder female rats.
- It exhibits pro-thrombotic activity
comparable to that of raloxifene in rats
- It has no effect on establishment/maintenance
of pregnancy in rat when administered
at 10 mg/kg/day oral dose on days 1-7
post-coitum, covering the entire pre-,
peri- and immediate post-implantation
periods
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| Application
and IPR status |
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- Being an anti-resorptive agent, it might
find use in the management of estrogen
deficiency (Type-I) osteoporosis.
- Indian (application no. 246/DEL/2004),
US (application no. 560NF02/US) and PCT
(application no. PCT/IB03/06178) patents
have been filed (International Publication
No.: WO 2004/087644
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