Changes
/* [[List of patents]] */
==== [[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.
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.
* '''STAT pathway'''
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.
=== Pathways associated with Anti Androgen===
[[Image:Slide1.GIF|thumb|center|700 px|Alopecia pathways]]
==== Players of WNT inhibition Pathway ====
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]
{| border="1" cellpadding="15", style="#008080"
!width="150" bgcolor=DodgerBlue|'''Patent no.'''
!width="200" bgcolor=DodgerBlue|'''Key compound'''
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''
|- style="height:10px"
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|GSK3
|-
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|GSK3
|-
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|CDK,GSK3
|-
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]
|bgcolor=LightCyan|Pyrimidine derivative
|bgcolor=LightCyan|GSK3
|-
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]
|bgcolor=LightCyan|Heterocyclic compounds
|bgcolor=LightCyan|AKT3, GSK-3, ERK2
|-
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives
|bgcolor=LightCyan|GSK3
|-
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]
|bgcolor=LightCyan|Aza-oxindole derivatives
|bgcolor=LightCyan|GSK3, AKT, PKC
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives
|bgcolor=LightCyan|GSK3
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles
|bgcolor=LightCyan|GSK3, AKT, PKC
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]
|bgcolor=LightCyan|Pyrazolon derivatives
|bgcolor=LightCyan|GSK3, ß-catenin
|-
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt
|-
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]
|bgcolor=LightCyan|Peptide sequence
|bgcolor=LightCyan|ß-catenin
|-
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]
|bgcolor=LightCyan|Peptide sequence
|bgcolor=LightCyan|a-catenin, ß-catenin
|-
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]
|bgcolor=LightCyan|Peptide sequence LXXLL
|bgcolor=LightCyan|ß-catenin
|-
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]
|bgcolor=LightCyan|Peptide sequence LXXLL
|bgcolor=LightCyan|ß-catenin
|}
==== Role of Pyrazole compounds in Wnt Pathway====
'''Pyrazole'''
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.
* Structurally related compounds are pyrazoline and pyrazolidine.
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]
==== GSK3 inhibition by pyrazole compounds ====
[[Image:bold3.jpg]]
{| border="1" cellpadding="2", style="#008080"
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]
[[Image:US6989385.jpg]]
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]
[[Image:US6664247.jpg]]
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]
[[Image:WO2005012256.jpg]]
|-
|bgcolor=lightcyan|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
|bgcolor=lightcyan|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).
|bgcolor=lightcyan|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''':
[[Image: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'''
[[Image: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''':
[[Image: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''':
[[Image: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''':
[[Image:pyrazol5.jpeg]]
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]
[[Other derivates for alopecia]]
==== GSK-3 Inhibition Mechanism - Phosphorylation====
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified.
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.
'''[[More details on GSK-3]]'''
'''Key points'''
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]
'''GK3 Inhibition:'''
* GSK3 is regulated by phosphorylation.
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP.
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation.
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation.
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom.
'''Serine - pyrazole reaction'''
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive.
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]
# inactivation of GSK-3 through serine phosphorylation
# activation of GSK-3 through tyrosine phosphorylation
# inactivation of GSK-3 through tyrosine dephosphorylation
# Covalant modifications of substrates through priming phosphorylation
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins
# targeting of GSK-3 to different subcellular localizations
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity
# integration of parellel signals conveyed by a signal stimulus.
'''Key Finding'''
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]
=== Pathway associated with anti-androgen ===
* Dihydrotestosterone
** Formed by peripheral conversion of testosterone by 5-alpha reductase
** Binds to androgen receptor on susceptible hair follicles
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]
==== Structure-Activity Relationships(SARs) ====
[[Image:SAR_map.gif|center|600px]]
=== 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.
[[image:vasodiator-rev.jpg|800 px|center]]
== Alopecia IPMap ==
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]
== Conclusions ==
* Hair loss medication is a very active area of research and intellectual property development.
* One of the most promising areas of development is the area of Anti-androgens.
* The top companies are Merck, L’Oreal and Smithkline.
