Selective oestogen receptor modulators

SELECTIVE ESTROGEN RECEPTOR MODULATORS

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Estrogen


That Nourishes & Nurtures

womanhood

The Feminine Hormone

Estrogen


Effects of Estrogen at Various Sites in the Body

Tissue Effect of Estrogen Stimulation

Clinical Effect of Stimulation

Clinical Effect of Absence of Stimulation

Bone Increased deposits of calcium into bone

Increased bone density Osteoporosis

Brain Blocks the release of ovarian estrogen

NoneHot flashes, sleep disorders, mood changes, problems with memory? Alzheimer’s disease??

BreastStimulates growth of breast tissue

Bigger breasts,? Increased risk of breast cancer, increased sensitivity of the breast,

Smaller breasts

Blood Clotting

Increased risk of blood clots No change in clotting

Blood Fats Increased HDL, decreased LDL, decreased Cholesterol,

Decreased HDL, increased LDL, increased Cholesterol

Skin Increased fat deposits in skin Softer skin Thinner skin, liver spots, dry skin

Uterus Increased stimulation of uterine lining and muscle

Heavier cycles, increased risk of uterine cancer

No periods

VaginaIncreased thickening of skin, better blood supply to tissue

Vaginal discharge, feelings of pelvic congestion

Dryness, vaginal infections, painful sex, incontinence of urine, pelvic weakness


Molecular Action of Estrogen

Adopted from George et al

hsp90 – heat shock protein90



Adopted from Stanley J Birge et al

AP I – activator protein

CRP – co regulator protein

ER – estrogen receptor

ERE – estrogen response element

Poly II – polymerase II

TATA- adenine-thymine-rich sequence important for gene transcription


Estrogen Receptor

Two types have been so far identified : -

and


Illustration by Anne Erickson


Estrogen Receptor Distribution

& -CNS, blood vessels, bone, heart, breast, ovary, uterus, testes, prostate

- Liver - Lungs, kidney, bladder,

intestines

Adopted from George GJM Kuiper et al

* Based on the level of ER mRNA levels

* Awaits confirmation till subtype specific monoclonal antibodies are available




homodimer homodimer & heterodimer

•Non-genomic effects

Adopted from George GJM Kuiper et al

Alternating estrogen signaling pathways


Molecular Action of EstrogenDifferent response in different

tissues

Adopted from Lewis J. Kleinsmith Ph.D, Donna Kerrigan M.S., Jeanne Kelly


Estradiol

Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer 2000; 89: 819.

Molecular Action of


SERM(Tamoxifen)


Molecular Action of


Estrogen Receptor Down regulator A Promising Area of Research


Molecular Action of


Mechanism of Tissue Response - Summary

Oestrogen Receptor Ligand Complex

Oestrogen Receptor

Ligand

E / SERM / PE/ERD

DNA Oestrogen Response element

Gene Transcriptio

n

Tissue Response

Coregulatory Proteins /

Agonistic & or

Antagonistic

AF 1 & 2


Selective Ostrogen Receptor Modulators

Estrogens

Anti Estrogens

SERMs

SERMs- designed to act in specific ways at each of the oestrogen receptor sites in different tissuesERDR

Phytoestrogens


Designer drugs which exhibit tissue specific desirable Estrogenic &

Antiestrogenic actions in different tissues

“Designer Estrogens”“Fantasy Estrogens”

They have the potential of providing a new paradigm for maintaining the

health of women.



• Mer 25 (1958)

• Clomiphene

1. Tamoxifen• Toremifene• Droloxifene• Iodoxifene

2. Raloxifene

3.Ormeloxifene

As of Today



The Ideal Selective Ostrogen Receptor Modulator

The perfect SERM

The ideal SERM is one that prevents bone loss, has no risk of uterine or breast cancer, a +ve effect on lipids & cardiovascular system, relieves PMS and maintains cognitive function of the brain

The Search goes on

Adopted from – Rita de Cassia M Dardes & V Craig Jordan


The Ideal Selective Ostrogen Receptor Modulator

The perfect SERM

TISSUE

Endometrium

Breast

Vagina

Bone

Liver/CVS

CNS

Perfect

AE

AE

E

E

E

EE-Estrogenic, AE-Anti Estrogenic

Tamo

E

AE

AE

E

E

AE

Ralo

AE

AE

AE

E

E+

E?

Ormelo

AE

AE

E

E

E

E

The Search goes on


Tamoxifen

• The first true SERM.• In use for breast cancer treatment

since 1968, 10m patient use years.• Approved for prophylactic use

in1997.• Beneficial effect on osteoporosis.• Effect on CVS +?

– Lipid profile +.


Tamoxifen

• Has many undesirable E / AE actions.– E in uterus – risk of End. Cancer.– Alleged as a carcinogen.– AE in vagina, CNS?

• Unsatisfactory safety/toxicity profile.• Gave boost to the continued research

for SERMs. • Under evaluation-star trial-6/99,

22000 women for 5-10 yrs.


Raloxifene

• Originally approved (1998) for use for treatment and prevention of osteoporosis.

• Subsequently (1999) approved for breast cancer prevention after ‘MORE’ study

• Improved safety profile than Tamoxifen

• Cardiovascular effects are unequivocal & under evaluation.


Raloxifene

Risk of venous thromboembolism• No effect on endometrium. AE on

vagina • Effect on CNS?. No improvement in

cognitive function• Does not relieve PM hot flashes • Possible future use as HRT??• Is on evaluation- STAR trial


ORMELOXIFENE

The individual elements of the molecular structure give a tissue selectivity- different

DNA transcriptions in different tissues

Estrogen agonist

Estrogen antagonist

Chemical Name- Trans -7-methyl-2-2-dimethyl-3-

phenyl-4(4-(2-pyroldinoethoxy)phenyl(-chroman hydrochloride), related to centchroman

The perfect SERM


The perfect SERM

ORMELOXIFENE

• Enhanced tissue selectivity– Basic amine side chain – uterine AE action– Pyrolidine base – highest degree of

antagonistic action– Benzopyran group – agonistic action &

binding affinity• Very strong binding affinity to ER

– Quick & potent action• Slow nuclear build up & prolonged

retention of ER– Long half life & prolonged action


An optimally designed potent SERM with Varied Tissue ResponseOestrogen Antagonist in UTERUS &

BREASTMild Oestrogenic action on Vagina, Bone mineral density, CNS and Serum LipidsNo action on Hypothalamic Pituitary Ovarian function, Thyroid, Adrenal.

The perfect SERM

ORMELOXIFENE

No Progestational, Androgenic or Antiandrogenic properties


ORMELOXIFENE

Special benefit in perimenopausal women – Relief of PMS

Currently indicated for the treatment of Dysfunctional Uterine Bleeding at ANY AGE.Not suitable for women desiring pregnancy

Approved for inclusion in National Family Welfare Program, for social marketing.

The perfect SERM


ORMELOXIFENE

•Contraindicated in –

•H/O recent liver dysfunction or clinical jaundice

•PCOD•Cervical Dysplasia & Chronic

Cervicitis•Hypersensitivity to the drug•Allergic conditions•Nursing mothers •Chronic illness

The perfect SERM


ORMELOXIFENE

Has an excellent safety profile,very well tolerated &

practically without any undesirable side effects

Easy to administer - 60mg tablet twice a week ( Sunday &

Wednesday) for 12 weeks followed by one tablet of 60mg once

weekly

The perfect SERM


ORMELOXIFENE

Currently being evaluated for use in the treatment and prevention of: -•Breast Cancer•Osteoporosis Possible future use: -•Menopause management•Fibromyoma•Endometriosis and Adenomyosis•Contraceptive

The perfect SERM


ORMELOXIFENE

WARNING: -

Indian contribution

Not introduced in the international arena

Not approved by FDA

Not yet fully evaluated - extensive clinical trials needed

The perfect SERM


““There is no cure for birth and There is no cure for birth and death save to enjoy the death save to enjoy the

interval”interval”--Santayana--Santayana

Selective Estrogen Receptor Modulators promise to make the

interval really enjoyable for women, though the final words on

Mode Of Action of Estrogen, Estrogen Receptors and SERMs are

yet to be said.


Women have reason to say

SERMs have the potential of providing a new paradigm for

maintaining the health of women.

Selective oestogen receptor modulators

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