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Prostaglandin D2 Receptor Antagonists for Treating

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Prostaglandin D2 Receptor Antagonists for Treating (19) TZZ Z¥_T (11) EP 2 037 967 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/60 (2006.01) A61K 31/415 (2006.01) 07.12.2016 Bulletin 2016/49 A61K 31/215 (2006.01) A61K 31/19 (2006.01) (21) Application number: 07809581.7 (86) International application number: PCT/US2007/014031 (22) Date of filing: 15.06.2007 (87) International publication number: WO 2007/149312 (27.12.2007 Gazette 2007/52) (54) PROSTAGLANDIN D2 RECEPTOR ANTAGONISTS FOR TREATING ANDROGENETIC ALOPECIA PROSTAGLANDIN D2 REZEPTOR ANTAGONISTEN ZUR BEHANDLUNG ANDROGENER ALOPEZIE ANTAGONISTES DU RÉCEPTEUR DE PROSTAGLANDINE D2 POUR LE TRAITEMENT DE L’ALOPECIE ANDROGÈNE (84) Designated Contracting States: US-A1- 2005 014 729 AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • KIM JERI ET AL: "Suppression of prostate tumor SI SK TR cell growth by stromal cell prostaglandin D Designated Extension States: synthase-derived products" CANCER AL BA HR MK RS RESEARCH, vol. 65, no. 14, July 2005 (2005-07), pages 6189-6198,6178, XP002581508 ISSN: (30) Priority: 16.06.2006 US 814041 P 0008-5472 18.09.2006 US 845161 P • ISHIZUKA T ET AL: "RAMATROBAN (BAY U 3405): A NOVEL DUAL ANTAGONIST OF TXA2 (43) Date of publication of application: RECEPTOR AND CRTH2, A NEWLY IDENTIFIED 25.03.2009 Bulletin 2009/13 PROSTAGLANDIN D2 RECEPTOR" CARDIOVASCULAR DRUG REVIEWS, NEVA (60) Divisional application: PRESS, BRANFORD, CT, US, vol. 22, no. 2, 1 June 16196670.0 2004 (2004-06-01), pages 71-90, XP008078031 ISSN: 0897-5957 (73) Proprietor: The Trustees of The University of • GOVONISTEFANO ET AL: "The Cycloxygenase-2 Pennsylvania inhibitor SC58236 is neuroprotective in an in vivo Philadelphia, PA 19104-6283 (US) model of focal ischemia in the rat" NEUROSCIENCE LETTERS, vol. 303, no. 2, 4 May (72) Inventors: 2001 (2001-05-04), pages 91-94, XP002581509 • GARZA, Luis ISSN: 0304-3940 Philadelphia, PA 19103 (US) • LESLIE K S ET AL: "Alopecia universalis treated • COTSARELIS, George with bone morphogenetic protein?" BRITISH Berwyn, PA 193212 (US) JOURNAL OF DERMATOLOGY, WILEY-BLACKWELL PUBLISHING LTD, GB (74) Representative: Dawson, Elizabeth Ann et al LNKD- DOI:10.1111/J.1365-2133.2005.07011.X, Pearl Cohen Zedek Latzer Baratz UK LLP vol. 154, no.1, 1 January 2006 (2006-01-01), pages 16 Upper Woburn Place 190-191, XP002390573 ISSN: 0007-0963 London WC1H 0BS (GB) (56) References cited: EP-A1- 1 666 473 EP-A2- 0 249 193 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 037 967 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 037 967 B1 • GARZA L A ET AL: "Balding scalp possesses a • ARIES M -F ET AL: "Myrtacine regulates normal complement of follicle stem cells and arachidonic acid cascade, cyclooxygenase, and geneexpression changes implicate inflammation lipoxygenase pathways in human keratinocytes: as causative" JOURNAL OF INVESTIGATIVE interest in the treatment of inflammatory acne DERMATOLOGY, vol. 126, no. Suppl. 1, April 2006 disease" JOURNAL OF INVESTIGATIVE (2006-04), page 99, XP002581510 & 67TH DERMATOLOGY, vol. 129, no. 3, March 2009 ANNUAL MEETING OF THE (2009-03), page 805, XP002581512 & ANNUAL SOCIETY-FOR-INVESTIGATIVE-DERMATOLOG CONGRESS OF THE Y; PHILADELPHIA, PA, USA; MAY 03 -06, 2006 FRENCH-SPEAKING-SOCIETY-FOR-DERMATO ISSN: 0022-202X LOGICAL -RES EARCH; TOULOUSE, FRANCE; • ROSENBLUM M D ET AL: "CD200, a ’’no danger’’ SEPTEMBER 12, 2008-SEPTEMBER 1 ISSN: signal for hair follicles" JOURNAL OF 0022-202X DERMATOLOGICAL SCIENCE, ELSEVIER • GARZA L A ET AL: "CD200(high) SCIENCE PUBLISHERS, SHANNON, IR LNKD- alpha-6-integrin(high) keratinocytes possess DOI:10.1016/J.JDERMSCI.2005.11.003, vol. 41, characteristics of early stem cell progeny, are no. 3, 1 March 2006 (2006-03-01), pages 165-174, depleted in androgenetic alopecia, and localize XP025100908 ISSN: 0923-1811 [retrieved on to the bulge and secondary hair germ" JOURNAL 2006-03-01] OF INVESTIGATIVE DERMATOLOGY, vol. 128, • PETTIPHER ROY ET AL: "Antagonism of the no. Suppl. 1, April 2008 (2008-04), page S153, prostaglandin D2 receptors DP1 and CRTH2 as XP002581513 & INTERNATIONAL an approach to treat allergic diseases" NATURE INVESTIGATIVE DERMATOLOGY MEETING; REVIEWS. DRUG DISCOVERY, NATURE KYOTO, JAPAN; MAY 14 17, 2008 ISSN: PUBLISHING GROUP, GB LNKD- 0022-202X DOI:10.1038/NRD2266, vol. 62, no. 4, 1 April 2007 (2007-04-01), pages 313-325, XP002520111 ISSN: 1474-1784 • GARZA L A ET AL: "Evidence that Prostaglandin D-2 contributes to development of Androgenetic Alopecia" JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol. 129, no. Suppl. 1, April 2009 (2009-04), page S98, XP002581511 & 69TH ANNUAL MEETING OF THE SOCIETY-OF-INVESTIGATIVE-DERMATOLOGY; MONTREAL, CANADA; MAY 06 -09, 2009 ISSN: 0022-202X 2 EP 2 037 967 B1 Description FIELD OF INVENTION 5 [0001] This invention relates to a prostaglandin D2 receptor (DP receptor) antagonist for use in treating androgenetic alopecia (AGA). BACKGROUND OF THE INVENTION 10 [0002] In normal scalp, hair follicles (HF) constantly cycle between a growing stage (anagen), an involutional stage (catagen), and then a dormant stage (telogen). The length of the hair is determined by the duration of anagen. Thus, scalp follicles stay in anagen for 2-7 years, while non-scalp follicles typically remain in anagen for much shorter times. The caliber of the hair shaft and the cycling of the follicle are thought to be under control of the dermal papilla, a cluster of inductive mesenchymal-derived cells located at the base of the follicle. Anagen onset appears to be triggered by 15 mesenchymal-epithelial interactions between the dermal papilla cells and nearby hair follicle stem cells in the bulge, which is located at or near the insertion of the arrector pili muscle. Bulge cell progeny generate the new lower anagen hair follicle at anagen onset and contribute cells to the epidermis after wounding. [0003] Androgenetic alopecia (AGA) remains enigmatic. Often, AGA is characterized by conversion of large "terminal" follicles into "miniaturized" follicles that resemble the vellus follicles of the prepubescent face. AGA often results in an 20 increase in the proportion of hair follicles in telogen at the expense of follicles in anagen. Often, mild fibrosis replaces follicles in long-standing alopecia. Hypotheses to explain AGA include hormonal, genetic, and inflammatory insults. [0004] EP 1666473 A1 (Ono Pharmaceutical Co.) discloses carboxylic acid compounds of Formula I as described therein which are antagonists of the DP receptor, and their use for the prevention or treatment of conditions including acne, allergic disease, systemic mastocytosis, disorders accompanied by systemic mast cell activation, anaphylactic 25 shock, bronchoconstriction, urticaria, eczema, diseases accompanied by or as a result of itching, inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, cerebrovascular accident, chronic rheumatoid arthritis, pleurisy, and ulcerative colitis. EP 0249193 discloses a known treatment for androgenetic alopecia. SUMMARY OF THE INVENTION 30 [0005] This invention provides a prostaglandin D2 receptor (DP receptor) antagonist for use in treating androgenetic alopecia (AGA) in a subject. [0006] In an embodiment, the prostaglandin DP receptor antagonist is a prostaglandin D2 receptor 2 (DP2/CRTH2 receptor) antagonist. 35 [0007] In an embodiment, the subject is also administered a pro-hair growth prostaglandin selected from a prostaglandin E1, a prostaglandin E2, a prostaglandin F2a; or an analogue thereof. [0008] The present invention also provides the use of a prostaglandin DP receptor antagonist in the preparation of a pharmaceutical composition for treating androgenetic alopecia (AGA) in a subject. [0009] The prostaglandin DP receptor antagonist may be a prostaglandin D2 receptor 2 (DP2/CRTH2 receptor) an- 40 tagonist. [0010] In an embodiment, the pharmaceutical composition further comprises a pro-hair growth prostaglandin selected from a prostaglandin E 1, a prostaglandin E2, a prostaglandin F2a; or an analogue thereof. BRIEF DESCRIPTION OF THE FIGURES 45 [0011] Figure 1: A. Histology of AGA and Immunohistology of KRT15 in bald scalp. Hematoxylin and eosin stained tissue sections of haired (A) and bald (B) scalp photographed at same magnification exhibit large terminal hair follicle and 50 miniaturized follicle. Note anagen follicle extending to subcutaneous fat in A and only to level of arrector pili muscle (apm) in B. (C) Immunohistology of sections of terminal hair follicle (thf) and miniaturized hair follicle (mhf), both staining for the bulge stem cell marker KRT15 (brown stain, arrows), indicating presence of stem cell compartment in bald scalp. Staining in superficial epidermis (epi) is nonspecific. sg, sebaceous gland. (D-E). Scanning electron microscopy of showing hair follicle miniaturization in AGA (E) compared to haired scalp (D). 55 Figure 2, part 1- FACS analysis ofkeratinocyte isolated from scalp indicates stem cell numbers are similar in paired bald and haired scalp samples, but suprabasal cell numbers are decreased within the stem cell compartment of bald scalp. A) Lack of staining from isotype antibodies, yet virtually complete staining with an anti-actin antibody as 3 EP 2 037 967 B1 a control for permeabilization. Histogram with numbers of cells plotted as a percentage on the y axis, and intensity of staining on the x axis. B) KRT15 and FST co-localize. Pseudo-color plot of KRT15 staining intensity vs. FST staining intensity. Each point represents a cell counted, and the intensity of color is an indication of higher numbers of cells.
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