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Characterization of Selective and Potent Inhibitors of the Human Retinoic Acid

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Characterization of Selective and Potent Inhibitors of the Human Retinoic Acid Characterization of selective and potent inhibitors of the human retinoic acid hydroxylases CYP26A1 and CYP26B1 Brian Buttrick A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science University of Washington 2012 Committee: Nina Isoherranen Edward Kelly Joanne Wang Program Authorized to Offer Degree: Pharmaceutics TABLE OF CONTENTS Page List of Figures………………………………………………………………………….……………...………..ii List of Tables……………………………………………………………………………………………...……iii Chapter 1: Introduction ................................................................................................................ 1 1.1 General biology of retinoic acid............................................................................................. 2 1.2 Regulation of retinoic acid homeostasis and importance of CYP26 enzymes .... 4 1.3 Pharmacological effects of inhibitors of retinoic acid hydroxylation..................... 9 Chapter 2: Characterization of Inhibitors of Cytochrome P450 26B1 ..... 13 2.1 Introduction ............................................................................................................................... 14 2.2 Experimental ............................................................................................................................. 16 2.2.1 Chemicals ............................................................................................................................ 16 2.2.2 Synthesis ............................................................................................................................. 17 2.2.3 Incubation conditions for CYP26A1 and CYP26B1 and HPLC Analysis of RA Isomers and metabolites .................................................................................................. 17 2.2.4 CYP26A1 and CYP26B1 inhibition assay................................................................ 19 2.2.5 Inhibition Assay for CYP2B8, CYP2C9 and CYP3A4 ........................................... 20 2.2.6. CYP26B1 Homology Model. ........................................................................................ 21 2.3 Results .......................................................................................................................................... 22 2.3.1 Validation of CYP26B1 inhibition assay ................................................................. 22 2.3.2 Characterization of CYP26 isoform selectivity of known azole inhibitors of RA metabolism ............................................................................................................................ 23 2.3.3 Inhibition of CYP26B1 and CYP26A1 by RAR agonists ..................................... 24 2.3.4. CYP26B1 Homology Model. ........................................................................................ 26 2.4 Discussion ................................................................................................................................... 28 Chapter 3: Characterization of Inhibitors of Cytochrome P450 26A1 ..... 45 3.1 Introduction ............................................................................................................................... 46 3.2 Experimental ............................................................................................................................. 48 3.2.1 Chemicals ............................................................................................................................ 48 3.2.2 Synthesis ............................................................................................................................. 48 3.2.4 Inhibition assay ................................................................................................................ 48 3.3 Results .......................................................................................................................................... 49 3.4 Discussion ................................................................................................................................... 51 Chapter 4: Summary and Conclusions ............................................................................ 60 Bibliography ...................................................................................................................................... 61 i LIST OF FIGURES Figure Number Page 1. Metabolism of vitamin A ............................................................................................... 11 2. Effects of RAMBAs on in vivo concentrations on RA .................................................... 12 3. Characterization of 9cis-RA as a substrate of CYP26B1 ................................................ 35 4. Azole IC50’s and Kd’s with CYP26B1 ............................................................................... 36 5. Tazarotenic acid and tazarotene IC50’s ......................................................................... 37 6. NOH compounds ........................................................................................................... 38 7. CYP26B1 homology model ............................................................................................ 39 8. Tazarotene and Tazarotenic Acid docked into the CYP26B1 homology model ........... 40 9. IC50 change when a heterocycle is introduced to a molecule. ...................................... 59 10. The change in potency when a naphthyl group is substituted for a phenyl group. ... 58 ii LIST OF TABLES Table Number Page 1. IC50 values for CYP Panel with Azole inhibitors ............................................................ 41 2. IC50 values for RAR agonists containing a carboxylic acid with CYP26A1 and CYP26B1 42 3. IC50 values for RAR agonists containing an ester with CYP26A1 and CYP26B1 ............ 43 4. IC50 values for RAR agonists with a CYP2C8, CYP2C9, and CYP3A4 .............................. 44 5. Lead inhibitors for CYP26A1 selective inhibition .......................................................... 56 6. Acidic compounds designed to target CYP26A1 selective inhibition ........................... 57 iii 1 Chapter 1: Introduction (Submitted to Current Topics in Medicinal Chemistry) 2 1.1 General biology of retinoic acid Retinoic acid (RA) is the active metabolite of vitamin A (retinol) and a critical signaling molecule during embryonic development and post-natal life in all chordates. Chemically, RA exists as at least five different isomers: all-trans-RA (atRA), 9-cisRA, 13-cisRA, 11-cisRA and 9,13-dicisRA (Figure 1)1, 2. Of these, endogenous atRA, 13-cisRA, and 9,13-dicisRA are commonly found in biological matrices whereas 9-cisRA is undetectable in many tissues 3 and very low in human serum4. 11-cisRA is not detected in human serum or reported in animal tissues 3, 4. However, 11-cis-retinal, the precursor of 11-cisRA is a necessary component for vision 2. Endogenous RA isomers are important in maintaining general health. They are involved in maintenance of healthy skin, epithelia and immune system, in regulating glucose stimulated insulin secretion3, 5, 6, in embryonic development7, in stem cell differentiation8, in neuronal differentiation9, and in spermatogenesis6. RA isomers also regulate cell cycle and apoptosis. In early studies, RA deficiency was shown to cause hyperkeratinization in rodents 10 and fetal malformations including blindness and lack of eyes in pigs11. Excessive intake of vitamin A on the other hand leads to a common syndrome known as hypervitaminosis A. Symptoms of hypervitaminosis A include erythema, weight loss, hair loss, changes to skin and mucus membranes, bone pain, and teratogenicity12. The exact role of each RA isomer in the above processes is not fully understood. Generally, atRA is considered to be the biologically active isomer of RA, but 9-cisRA and 13-cisRA also appear to have biological activity and are marketed as drugs13. The biological importance of 9,13-dicisRA is unclear; it is inactive in cell culture 14,15and 3 did not support growth in vitamin A deficient rats16. As a drug, atRA is approved for use in acute promyelocytic leukemia (APL) 17and is used off-label in other cancers. Isotrentinoin (13-cisRA) is approved for the treatment of acne, and high risk neuroblastoma in children18. Alitrentinoin (9-cisRA) is approved for use as a topical treatment for Kaposi’s sarcoma 13 and is used to treat chronic hand eczema unresponsive to other treatments19. The use and development of RA isomers and synthetic retinoids for treatment of cancer and metabolic disease has been recently reviewed by others 13. While the exact biochemical mechanisms of how retinoids function in cancer and in dermatological diseases are not known, the therapeutic potential of retinoids is well established. The biological activity of retinoids is largely mediated by their binding to the nuclear retinoic acid receptors (RARs)20,21,22, but other mechanisms by which RA isomers cause changes in cell cycle and differentiation have also been shown23,24. Binding of retinoids to RARs results in increased transcription of target genes 17 and, hence, the observed effects of RA on gene transcription are dependent on the cellular concentrations ofatRA as well as on the expression levels of RAR isoforms. There are three RAR isoforms, RARα, RARβ and RARγ, which each play different roles in the body. However, RA and its isomers bind to all three isoforms25. As such, specific agonists and antagonists of each RAR isoform have been developed and evaluated for various therapeutic
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