US 20050203111A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0203111A1 David (43) Pub. Date: Sep. 15, 2005 (54) COMPOSITIONS AND METHODS FOR Publication Classification PREVENTING AND TREATING SKIN AND HAIR CONDITIONS (51) Int. Cl.' .................. A61K 31/517; A61K 31/4745; A61K 31/41.96 (75) Inventor: Nathaniel E. David, San Francisco, CA (52) U.S. Cl. ...................... 514/266.1; 514/383; 514/357; (US) 514/396; 514/303 Correspondence Address: (57) ABSTRACT WILSON SONS IN GOODRICH & ROSAT 650 PAGE MILL ROAD The present invention discloses compositions and methods PALO ALTO, CA 94304-1050 (US) for the prevention and treatment of skin and hair diseases, Such as, for example, alopecia, psoriasis, and keloids. In one (73) Assignee: VVII NewCo 2003, Inc., Menlo Park, embodiment, the present invention discloses a method for CA (US) preventing and treating hair loSS by applying locally to a region lacking hair a p38C. MAP kinase inhibitor. The p38C. (21) Appl. No.: 10/799,867 MAP kinase inhibitor is preferably formulated as a gel, ointment, Spray or Solution that can be applied topically, (22) Filed: Mar. 12, 2004 transdermally, or Subcutaneously to the targeted region. Patent Application Publication Sep. 15, 2005 Sheet 1 of 4 US 2005/0203111A1 F.G. 1 Patent Application Publication Sep. 15, 2005 Sheet 2 of 4 US 2005/0203111 A1 '', FIG. 2 Patent Application Publication Sep. 15, 2005 Sheet 3 of 4 US 2005/0203111A1 FIG. 3 Patent Application Publication Sep. 15, 2005 Sheet 4 of 4 US 2005/0203111A1 FIG. 4 US 2005/0203111A1 Sep. 15, 2005 COMPOSITIONS AND METHODS FOR 0008. In particular, the present invention relates to meth PREVENTING AND TREATING SKIN AND HAIR ods for treating and/or preventing hair loSS in a patient by CONDITIONS administering to Such patient an effective amount of one or more p38 inhibitors. The p38 inhibitors are preferably BACKGROUND OF THE INVENTION administered locally to a region requiring hair regeneration 0001. The present invention relates to compositions and or prevention of hair loss. More preferably, the p38 inhibi methods for preventing and treating skin and hair condi tors are administered topically, transdermally or Subcutane tions. ously. 0002 The skin is the second largest organ in the body and 0009. The present invention also relates to methods for is of primary importance to the Survival of a mammal. The treating and/or preventing skin conditions, Such as, for skin rests on Subcutaneous tissue largely composed of a example, Vitiligo and acne, and acne Scars by administering loose mesh of collagen fiber, fat cells, and muscle tissue. An to Such a patient an effective amount of one or more p38 average adult has over 3,000 Square inches of skin Surface inhibitors. Again, the p38 inhibitors are preferably admin area. Overall, fat-free skin accounts for at least 6 percent of istered locally. More preferably, the p38 inhibitors are an individuals total weight. The density of structures in the administered topically, transdermally or Subcutaneously. skin varies considerably depending on its location. But on 0010 Examples of p38 inhibitors include, but are not average, one Square centimeter of skin contains about 10 limited to, pyridinylimidazoles, Substituted pyrazoles, Sub hair follicles, 15 Sebaceous glands, 100 Sweat glands, half a Stituted pyridyls, quinazoline derivatives, aryl ureas, het meter of blood vessels, 2 meters of nerves with 3,000 eroaryl analogues, Substituted imidazole compounds, and sensory cells at the ends of nerve fibers, 200 nerve endings to record pain, 25 pressure receptors for the perception of Substituted triazole compounds. tactile Stimuli, 2 Sensory receptorS for cold, and 12 Sensory receptors for heat. BRIEF DESCRIPTION OF THE DRAWINGS 0003. The skin of a mammal is derived from ectoderm 0011. The novel features of the invention are set forth and mesoderm layers of an embryo. These two layers give with particularity in the appended claims. A better under rise to the epidermis and dermis, respectively. The ectoderm Standing of the features and advantages of the present and mesoderm layerS also give rise to specialized append invention will be obtained by reference to the following ages including Sensory nerves, Sweat glands, and hair fol detailed description that sets forth illustrative embodiments, licles. Thus, the skin and hair follicles are physiologically in which the principles of the invention are utilized, and the related. accompanying drawings of which: 0004. The skin serves various functions including, but 0012 FIG. 1 illustrates p38 inhibitor BIRB-796. not limited to, providing flexible physical Support, main 0013 FIG. 2 illustrates p38 inhibitor CNI-1493. taining constant temperature, excreting waste materials. Such as Salts and water, producing Vitamins by photochemical 0014 FIG. 3 illustrates p38 inhibitor RDP-58. reactions in the skin, Sensory functions, providing protection 0.015 FIG. 4 illustrates p38 inhibitor VX-745. against the excesses of ultraViolet light by pigmentation Such as melanin, providing protection of organs, preventing INCORPORATION BY REFERENCE absorption of unwanted or dangerous chemicals, and pro Viding an immunological defense. 0016 All publications and patent applications mentioned in this specification are herein incorporated by reference to 0005 Hair serves similar functions. The main function of the same extent as if each individual publication or patent hair is to provide protection against heat loSS. Hair may also application was specifically and individually indicated to be act to protect the epidermis from minor abrasions and from incorporated by reference. ultraViolet light. In addition, hair may provide indication of Sexual development. It may also play an important role in DETAILED DESCRIPTION OF THE attracting mates by indicating the general health and Vitality INVENTION of an individual. Furthermore, certain body parts may con tain Specialized hairs. Specialized hair Such as eyebrows and 0017. The present invention relates to compositions and eyelashes act to protect the eyes by channeling or Sweeping methods for preventing and treating skin and hair condi away fluids, dust and debris. Nasal hair act to trap air borne tions. The compositions of the present invention include at foreign particles before they reach the lungs. These special least one p38 MAP kinase (referred to herein as “p38”) ized hairs and other hair follicles have a highly developed inhibitor. The term “p38” as used herein, refers to all nerve network around them that can provide Sensory, tactile isoforms, splicing variants, homologues, fragments, metabo information about the environment. lites, prodrugs, and mimetics of p38, both naturally occur ring and synthetic. The term “p38 inhibitor,” as used herein, 0006 There are many conditions that affect skin and hair. refers to any agent that blocks, diminishes, inhibits, hinders, Such conditions include, but are not limited to, acne, Scar limits, decreases, reduces, restricts or interferes with the ring, Vitiligo, and hair loSS. It would be desirable to identify activity of endogenous p38. A p38 inhibitor can also func novel methods and compositions for preventing and/or treat tion upstream or downstream of p38 to downregulate the ing skin and hair conditions. amount or function of p38. SUMMARY OF THE INVENTION 0018 p38 is a stress-activated protein. p38 can be 0007. The present invention relates to methods for treat activated by, for example, UV light, heat, chemical ing and/or preventing skin and hair conditions. or osmotic shock, IL-1, TNF, and endotoxins. p38 is US 2005/0203111A1 Sep. 15, 2005 one of three families of MAP kinases: the extracel 0022. To date, there have been several mechanisms and lular regulated kinases (ERKs), the c-Jun NH2 ter numerous compounds Suggested for the inhibition of p38. minal kinases or StreSS activated protein kinases Compounds that have been Suggested for the inhibition of (JNKS or SAP kinases), and the p38 MAP kinases. A p38 include pyridinylimidazoles. See Young P. R., et al., distinguishing feature of each of these kinase fami (1997).J. Biol. Chem. 272, 12116-12121; see also Bender, P. lies is that the ERKS have a TEY amino acid motif, E., (1985) J. Med. Chem. 28, 1169-1177. Examples of the JNKS or SAP kinases have a TPY amino acid pyridinylimidazoles that may inhibit p38 include 6-(4'- motif, and the p38 MAP kinases have a TGY amino fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo(2,1-b)- acid motif. thia Zole and its metabolites (Sulfoxide, Sulfone), analogues, 0019. The p38 family includes four different isoforms: fragments, and mimetics. It has further been Suggested that p38C. MAP kinase (p38c), p38B MAP kinase (p38 B), p38Y the minimal structure of pyridinylimidazoles, 4-(pyridin-4- MAP kinase (p38Y), and p388 MAP kinase (p388). p38C. is yl)-5-phenylimidazole, may be sufficient to inhibit p38. See expressed ubiquitously. A shorter C-terminal truncated form Gallagher, TF, et al., (1997) Bio-Org. Med Chem. 5, 49-64. of p38C, known as Mxi-2 has also been identified in a yeast 0023 Certain 1,5-diaryl-substituted pyrazole compounds two-hybrid Screen based on its association with the tran have also been Suggested as p38 inhibitors. Such Substituted scription factor Max. p38B has been shown to have an pyrazole compounds are disclosed in U.S. Pat. No. 6,509, additional isoform, p3832 that lacks the 8 amino acid 361, assigned to Pharmacia Corporation, incorporated insertion found in p38B. Between these two variants p3832 herein by reference for all intended purposes. Additional is believed to be the major form as p38B is catalytically less pyrazole derivatives that inhibit p38 are disclosed in U.S. active. p38Y and p388 are 63% and 61% identical to p38C, Pat. No. 6,335,336, assigned to G.D. Searle & Co., incor respectively. p38Y is expressed predominantly in skeletal porated herein by reference for all intended purposes. muscle wherein p38ö is expressed predominantly in testes 0024.