(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date _ . _ ... _ 12 April 2012 (12.04.2012) WO 2012/048204 A2 (51) International Patent Classification: (74) Agents: TYLER-CROSS, Ruth, E. et al; Whitham, A61K 47/48 (2006.01) A61K 31/426 (2006.01) Curtis, Christofferson & Cook, P.c, 11491 Sunset Hills A61K 47/30 (2006.01) A61K 31/505 (2006.01) Road, Suite 340, Reston, VA 20190 (US). A61K 9/127 (2006.01) A61K 31/573 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US201 1/05523 1 AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 7 October 201 1 (07.10.201 1) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (25) Filing Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (26) Publication Langi English NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (30) Priority Data: RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, 61/391,1 77 8 October 2010 (08.10.2010) US TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): VIR¬ GINIA COMMONWEALTH UNIVERSITY [US/US]; (84) Designated States (unless otherwise indicated, for every 800 East Leigh Street, Suite 113, Richmond, VA kind of regional protection available): ARIPO (BW, GH, 23298-0568 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, (72) Inventors; and RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, (75) Inventors/ Applicants (for US only): WALSH, Scott, W. DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, [US/US]; 8900 Whistling Swan Road, Chesterfield, VA LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, 23838-8937 (US). GERK, Phillip, M. [US/US]; 10939 SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, Emerald Rock Lane, Mechnicsville, VA 23116-5865 GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (US). WANG, Meng [CN/US]; 104 West Franklin Street, Room 905, Richmond, VA 23220-5010 (US). LANDS- Published: BERG, Andrew, K. [US/US]; 264 Eagle Drive, Unit — without international search report and to be republished 102, Eagle-vail, CO 81620-3777 (US). upon receipt of that report (Rule 48.2(g)) (54) Title: PRODRUGS UTILIZING A TRANSPORTER DIRECTED UPTAKE MECHANISM Therapeutic aaent (such as lopinavir) Covalent linkage (such as ester bond) Spacer chain (such as C2-0-C2) < Hvdrophilic group (such o as carboxylic acid, COOH) ∞ Figure 1 © (57) Abstract: Prodrugs comprising a lipophilic drug linked to a transport moiety that can be taken up by a fatty acid transporter are provided. The transport moiety comprises a lipid chain connected to a hydrophilic group (e.g. a carboxylic acid, a phosphate, o or a sphingosine-like moiety). Due to the presence of the transport moiety, the prodrugs are substrates for endogenous fatty acid transporter systems. The transport moiety thus serves as a carrier or targeting moiety to facilitate uptake of the entire prodrug com plex by endogenous fatty acid transporter systems, thereby moving the prodrug into cells and tissues where drug distribution and o effects are desired. Hydrolysis of the chemical linkage between the lipid-like moiety and the lipophilic drug releases the drug in an active form within the cells or tissues. PRODRUGS UTILIZING A TRANSPORTER DIRECTED UPTAKE MECHANISM DESCRIPTION BACKGROUND OF THE INVENTION Field of the Invention The invention relates to the delivery of prodrugs to a desired site of action via uptake by endogenous lipid transport mechanisms. The prodrugs comprise a drug (e.g. a large, lipophilic drug) linked, via a hydrolyzable chemical bond, to a transport moiety that causes the prodrug to be taken up by a fatty acid transporter. Background of the Invention The development of methods for the targeted delivery of drugs to a site of action in an active form is a desideratum in the medical field that warrants the expenditure of hundreds of millions of dollars each year. Technologies have been developed whereby moieties that enhance solubility, permeability and stability are attached to drugs, e.g. via ester linkages. Recently, patents have issued for transporter directed prodrug approaches which utilize, for example, peptide transporters such as hPEPTl/2, monocarboxylate transporters such as MCTl-4, and multivitamin transporters such as SMVT to enhance uptake of drugs from the gastrointestinal tract. See, for example, US patent 7,671,082 to Moher, and US patent applications 2003/0158089 to Gallop et al. and 2005/0025839 to Polli, the compete contents of each of which are hereby incorporated by reference. In these cases, a moiety that is readily taken up by a transporter protein and translocated across the cell membrane is attached to a drug of interest, and the entire drug-moiety complex is taken up by the transporter and delivered into the cell. However, these transporters have only a limited capacity to accept large, lipophilic compounds, such as certain promising compounds used in the treatment of cancer and HIV. United States patent application 20090123388 to Ganapathy et al. (Prodrugs of Short-Chain Fatty Acids and Treatment Methods) is based on the discovery that the ATB + amino acid transport system can be used to transport prodrugs comprising a neutral or cationic amino acid that has been modified to comprise a short-chain fatty acid moiety, such as butyrate or pyruvate, into affected cells where the short-chain fatty acids exert their beneficial effect. These prodrugs are useful for treatment of colon cancer, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lung cancer, cervical cancer, and cancers resulting from metastases from primary colon cancer sites. However, this prodrug system is also not designed to deliver large, lipophilic drugs. Sohma et al, (J. Med. Chem. 2003, 46, 4124-4135) describe the development of water soluble prodrugs of the V- protean inhibitor K -727 (amprenavir). The prodrugs comprise both amprenavir and a hydrophilic solubilizing moiety linked to drug via a self- cleaveable spacer. However, this study fails to suggest or take into account potentially advantageous transport mechanisms within cells or tissues. Matsumoto et al., [Bioorganic & Medicinal Chemistry 9 (2001) 417-430] describe prodrug forms of HIV protease inhibitors. However, this research group reached the conclusion that the presence of free carboxylic acids in the prodrug deterred penetration of the prodrug across the cell membrane. This may have been because they failed to recognize the importance of using a suitably ionizable group in the prodrug, or to take into account potentially advantageous transport mechanisms within cells or tissues. US patent 5,914,332 to Sham, et al. describes lopinavir derivatives, but does not show or suggest modifications of lopinavir which facilitate uptake into cells or tissues, or which take into account the time of bioavailabiltiy of the drug. There is an ongoing need to develop additional drug delivery strategies, particularly for large, lipophilic compounds. SUMMARY OF THE INVENTION The invention expands the realm of transporter-directed prodrug approaches to drug delivery, particularly the delivery of large, lipophilic molecules, by utilizing the previously unexploited fatty acid uptake and transporting system. According to the invention, a drug or molecule of interest is converted into a substrate for uptake by a fatty acid transporter by the attachment of a transport moiety, converting the drug to a prodrug that readily binds to and is taken up by the transporter. The transport moiety, which comprises a lipophilic spacer chain and a hydrophilic group, thus acts as a carrier or targeting moiety for uptake of the entire prodrug structure via the fatty acid transport system. Attachment of the drug to the transport moiety is generally via a chemical bond that is susceptible to hydrolysis. Therefore, once inside a cell or tissue of interest, the transport moiety is cleaved (hydrolyzed) from the prodrug structure, releasing the drug in an active form. In some embodiments, the prodrugs are advantageously ionizable at physiological H, at levels which provide suitable or reasonable prodrug halflives, having components with a pKa at or below 4.2. Because this prodrug system utilizes fatty acid transporters for uptake, the system is particularly useful for the delivery of drugs, especially large, lipophilic drugs, to areas of the body which were previously difficult to target, for example, the fetal placental unit, the central nervous system, gut-associated lymphatic tissue, the brain, and tumors. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Schematic representation of uptake of a prodrug of the invention via a fatty acid transport system into target cells or tissues. Figure 2A-I. Structures of exemplary HIV Protease Inhibitors (HIVPI's). A, amprenavir; B, darunavir; C, atazanavir; D, indinavir; E, lopinavir; F, nelfinavir; G, ritonavir; H, saquiinavir; I, tipranavir; Arrows show hydroxyl groups susceptible to conjugation to a lipid-like structure. Figure 3A-Y. Exemplary prodrugs. A, succinyl-lopinavir; , diglycolic (diacetic)-lopinovir; C, thiodiglycolic (thiodiacetic)-lopinavir; D, fumaryl-lopinavir; E, muconyl-lopinavir;