Alopecia - Hair Loss

Contents

Rationale


Introduction

Hair basics

Structure of Hair root and Hair bulb

What causes hair loss?

Survey results from Japan

Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed ?Male Pattern Baldness" or "Androgenetic Alopecia".


Types of alopecia

Androgenetic alopecia

Main causes

Some facts from Japan

(JICST-EPlus - Japanese Science & Technology)

IP activity over the years

The graph indicates:

IP Activity over years

Major players

Assignees with more than 20 patents
Assignees with fewer than 20 patents

Assignees currently active with more than 5 patents to their credit during 2000-2005.

Active Assignees

Taxonomy

Alopecia toxonomy.jpg

Interactive Taxonomy

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Treatment Approaches

Composition of treatment for causes are identified and categorized as follows:

Cause Treatment approach Pathways affected
Hormonal effect of androgen Anti-androgens Testosterone pathway
Reduction of blood circulation around hair follicle Vasodilators (eg. Minoxidil) NO/cGMP Pathway
Deactivation of hair matrix cells Hair matrix cells activator
  • Wnt pathway
  • STAT pathway
  • TGF beta/BMP Pathway
  • FGF Pathway
  • MAPK Pathway
  • NOTCH Pathway
  • Hedgehog Pathway

Anti-androgens

What causes hair loss?

How do anti-androgens treat hair loss?

Functions of Anti-androgen

Anti-androgen

Functions of Anti-androgen

IP Map for anti-androgen

Pat/Pub# Nature Composition Composition action
US20060009430

BLOTECH (2004)

Natural extracts Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans) Fatty acids ? Inhibit testosterone

Sterols - Mechanism of action unknown.

Quercetin results in cell growth cycle.

Beta-sitosterol reduce inflammation on scalp

US20060009427

WARNER LAMBERT(2004)

Organic compound New class of 4-cycloalkoxy benzonitrile derivatives and salts Acts as androgen receptor modulator and blocks formation of DHT.
US20050085467

WARNER LAMBERT(2004)

Organic compound New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives. The compounds inhibit, or decrease, activation of androgen receptor by androgens.
US20050118282

APHIOS Corp (2003)

Natural extracts Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives. Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.
US20060009429

Fundacion Pablo Cassara (2003)

Nucleotide Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond) Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle
US20030007941

PFIZER INC (2001)

Organic compound Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle
US20030073616

N/A (1995)

Peptides/nucleic acid Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein) Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor
EP0279010

KAO Corp (1987)

Natural extracts Walnut extract (leaves/pericarps) with an organic solvent Blocks formation of DHT

Minoxidil (Vasodilators)

What causes hair loss?

How does Minoxidil treat hair loss?

Functions of Vasodilators

Functions of Monoxidil source

IP Map for Vasodilators

Pat/Pub# Nature Composition Composition action
US20040157856

WARNER LAMBERT(2002)

Organic compound Benzopyran compounds Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers
US20050053572

LG HOUSEHOLD & HEALTH CARE(2001)

Natural extracts Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex) Promotes function of cell activity and dilates blood vessels

Double action (Anti-androgen + Vasodilator)

What is the problem with using only Anti-androgen therapy?

What is the problem with using only Vasodilator (or Minoxidil only) therapy?

How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?

Functions of (Anti-androgen + Vasodilators)

Anti-androgen and Minoxidil

Functions of (Anti-androgen + Vasodilators)

IP Map for (Anti-androgen + Vasodilators)

Pat/Pub# Nature Composition Composition action
US20060052405

N/A(2000)

Peptides Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp
US20050123577

L'OREAL(2000)

Peptides Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP
US6447762

COLOMER GROUP(1999)

Natural extract Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound) Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp

Hair matrix cell activator

Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.

What causes hair loss?


How does hair cell matrix activator treat hair loss?

Functions of Hair matrix cell activator

Hair matrix cell activator

Functions of Hair matrix cell activator

IP Map for Hair matrix cell activator

Pat/Pub# Nature Composition Composition action
US20020052498

SHISEIDO(1999)

Organic compound (2-substituted oxyphenyl) alkanamide derivative and its salt Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect
US20040071647

L'OREAL(1998)

Peptides Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle)

Technology mapping based on patents analyzed

IPMap: Composition nature matrix

Year Organic Compound Natural extracts Peptides Nucleotides Natural extract + Organic comp
2005 .... .... .... .... UNILEVER (1)
2004 WARNER (1) BLOTECH (1) .... .... KAO (1)
2003 WARNER (1) APHIOS (1) .... FUNDACION (1) ....
2002 WARNER (1) .... .... .... ....
2001 PFIZER (1) LG HEALTH-CARE (1) .... .... ....
2000 .... .... L?OREAL (1) / N/A (1) .... ....
1999 SHISEDIO (1) COLOMER (1) .... .... ....
1998 .... .... L?OREAL (1) .... ....
1995 .... .... N/A (1) .... ....
1987 .... KAO (1) .... .... ....
1982 UNILEVER (1) .... .... .... ....

Focus of patents

Focus of patents Patent no. Rec. no.
2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect. US20020052498 1
Thyromimetic compounds, and its role in treating hair loss US20030007941 2
Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT US20060009430 3
4-cycloalkoxy benzonitriles and its use as androgen receptor modulators US20060009427 4
Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity US20050118282 5
New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists US20050085467 6
Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders US20060009429 7
Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss US20030073616 8
Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor EP0279010 9
Stimulating hair growth using benzopyrans US20040157856 10
Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels. US20050053572 11
Compositions to prevent or reduce hair loss US20060052405 12
Prostaglandin EP-3 receptor antagonists for reducing hair loss US20050123577 13
Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth US6447762 14
Metalloprotease inhibitors to induce and/or stimulate the growth US20040071647 15
Method of decreasing sebum production and pore size US20050277699 16
Method for reducing sebum on the hair and skin US4529587 17

Technology focus

Technology focus

Distribution of patents

By patent types

Distribution based on patent types


By key ingredients

Distribution of key ingredients

By target disease

Distribution based on target diseases


Key ingredients vs. Target disease

Key ingredients vs. Target disease


Target species

Target species


Mode of administration

Mode of administration


Product type vs. Product form

Product type vs. Product form

Patents by target diseases

Target disease/ disorder Patent no. Rec. no.
Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness) US20020052498 1
Alopecia areata, male pattern baldness and female pattern baldness US20030007941 2
Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both. US20060009430 3
Inappropriate activation of the androgen receptor, acne, oily skin, alopecia US20060009427 4
Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity US20050118282 5
Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia US20050085467 6
Androgen-associated hair loss and androgen-skin related disorders. US20060009429 7
Androgenetic or androgenic alopecia or androgeno-genetic alopecia US20030073616 8
Diseases caused by testosterone (male-pattern alopecia) EP0279010 9
Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal US20040157856 10
Male pattern alopecia US20050053572 11
Alopecia, androgenic alopecia US20060052405 12
Hair loss US20050123577 13
Male pattern alopecia US6447762 14
Androgenetic, androgenic or androgenogenetic alopecia US20040071647 15
Curing other scalp related problems US20050244362 16


List of patents

Pathways and linkages

Pathways associated with hair matrix cell activation

Molecular mediators of hair follicle embryogenesis: Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.

Pathways associated with Anti Androgen

Alopecia pathways

Players of WNT inhibition Pathway

Wnt inhibition
Patent no. Key compound Players of inhibition
US6664247 Pyrazole compounds GSK3
US6989385 Pyrazole compounds GSK3
WO2005012256 Pyrazole compounds CDK,GSK3
US6974819 Pyrimidine derivative GSK3
US6743791 Heterocyclic compounds AKT3, GSK-3, ERK2
US20050277773 Pyrrolo[3,2-d]pyrimidine derivatives GSK3
US20040072836 Aza-oxindole derivatives GSK3, AKT, PKC
EP1477489 Pyrrolopyrimidine derivatives GSK3
WO0056710 3-(Anilinomethylene) oxindoles GSK3, AKT, PKC
WO2003011287 Pyrazolon derivatives GSK3, ß-catenin
US6924141 Lithium chloride, Wnt3/4/ 7 ß-catenin, GSK3, Wnt
US6706685 Peptide sequence ß-catenin
US6683048 Peptide sequence a-catenin, ß-catenin
US6677116 Peptide sequence LXXLL ß-catenin
US6303576 Peptide sequence LXXLL ß-catenin

Role of Pyrazole compounds in Wnt Pathway

Pyrazole

Pyrazole (C3H4N2)
Structurally related compounds

GSK3 inhibition by pyrazole compounds

Bold3.jpg

US6989385

US6989385.jpg

US6664247

US6664247.jpg

WO2005012256

WO2005012256.jpg

R1=T-Ring D, wherein

T is a valence bond and Ring D = 5-6 membered aryl or heteroaryl ring;

R2 = hydrogen or C1-4 aliphatic and R2'= hydrogen;

R3 = -R, -OR, or -N(R4)2, wherein R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -O-, -S-, or -NH-; and Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring

X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length;

R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02;

R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and

R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;

A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).

Inhibition by amine derivatives

Patent Number: US6989385 Applicant: Vertex Pharmaceuticals Incorporated Title: Pyrazole compounds useful as protein kinase inhibitors

Basic Structure:

Pyrazol1.jpeg

Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent

Patent Number: US7008948 Applicant: Vertex Pharmaceuticals Incorporated Title: Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors

Basic Structure

Pyrazol2.jpeg

Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent

Patent Number: US6977262 Assignee: Mitsubishi Pharma Corporation Title: Dihydropyrazolopyridine compounds and pharmaceutical use thereof

Basic Structure:

Pyrazol3.jpeg

Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent


Patent Number: US6664247 Assignee: Vertex Pharmaceuticals Incorporated Title: Pyrazole compounds useful as protein kinase inhibitors

Basic Structure:

Pyrazol4.jpeg

Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent


Patent Number: US2004224944 Assignee: VERTEX PHARMACEUTICALS INC Title: Pyrazole compounds useful as protein kinase inhibitors

Basic Structure:

Pyrazol5.jpeg

Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent

Other derivates for alopecia

GSK-3 Inhibition Mechanism - Phosphorylation

More details on GSK-3

Key points

GK3 Inhibition:

Phosphorylation mechanism source


Serine - pyrazole reaction

Serine and Pyrazole reaction source

Proposed mechanisms to regulate GSK-3 source

  1. inactivation of GSK-3 through serine phosphorylation
  2. activation of GSK-3 through tyrosine phosphorylation
  3. inactivation of GSK-3 through tyrosine dephosphorylation
  4. Covalant modifications of substrates through priming phosphorylation
  5. inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins
  6. targeting of GSK-3 to different subcellular localizations
  7. differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity
  8. integration of parellel signals conveyed by a signal stimulus.

Key Finding

Pathway associated with anti-androgen

5-alpha-reductase inhibition.jpeg

Structure-Activity Relationships(SARs)

SAR map.gif

Pathway associated with Minoxidil (vasodilators)

Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.

Vasodiator-rev.jpg

Alopecia IPMap

Dolcera IPMap for Alopecia



Patent activity in China

Treatment approaches

Treatment approach Patent number Priority year Assignee/Inventor
Vasodilators CN1772105 2005 ???
CN1772139 2005 ???
CN1569080 2003 ???
CN1506103 2002 ???
CN1403100 2001 ???
CN1165181 1996 ???
CN1031022 1988 ???????????
Hair matrix activator CN1463693 2002 ???
Anti-androgen + Vasodilator CN1150043 1996 ???

Details of treatment approaches

Patent number Patent title Treatment approach Composition nature Composition Composition action
CN1772105
YE MINGWEI (CN)
??? (2005)
Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn
????????????????????
Vasodilators Herbal extract Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower Promote blood circulation
CN1772139
WANG YAJIE (CN)
??? 2005
Alopecia areata treating medicine
?????????
Vasodilators Herbal extract Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc Promote blood circulation
CN1569080
TAN RUBIAO (CN)
??? 2003
Natural Chinese herb composition for treating alopecia and leucotrichia and its application
??????????????????????????
Vasodilators Herbal extract Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds Enhances the hair growth and healthier hairs
CN1463693
??? 2002
Hair growing preparation containing compound of Chinese medicine and Western medicine
????????????
Hair matrix activator Mixture of Herbal extracts and western medicine Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus?Minoxidil, Vitamins and derivative, cystine, serine, leucine. Better and faster hair growth
CN1506103
???2002
Hair follice activating liquid
?????
Vasodilators Herbal extract Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers Activates the hair-follicle and enhances the hair growth.
CN1403100
??? 2001
Trichogen and its prepn
??????????????
Vasodilators Herbal extract Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed Promote blood circulation and enhance hair growth
CN1165181
??? 1996
Washing free shampoo for nourishing and growing hair
????????
Vasodilator Vitamin composition Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo?geramineum Stimulate hair growth
CN1150043
??? 1996
Efficient low-side effect external use medicine for curing seborrheic baldness
????????????????????
Anti-androgen + Vasodilator Mixture of Herbal extracts and organic compounds Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth
CN1031022
??????????? 1988
Channel-stimulating and hair-growing hair shampoo
????????
Vasodilators Herbal extract + detergent Herbal extracts, Penetration media, Detergents. Increases the blood circulation under the scalp, reduces the hair los


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