US 200803 06098A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0306098 A1 Mutz et al. (43) Pub. Date: Dec. 11, 2008 (54) PHARMACOKINETICS OF PROTEASE Publication Classification INHIBITORS AND OTHER DRUGS (51) Int. Cl. A 6LX 3L/505 (2006.01) (76) Inventors: Mitchell W. Mutz, La Jolla, CA A63L/4353 (2006.01) (US); Jason E. Gestwicki, Ann C07D 49/12 (2006.01) Arbor, MI (US) C07D 239/04 (2006.01) A6IP3 L/18 (2006.01) Correspondence Address: (52) U.S. Cl. ............ 514/274: 514/291; 546/90; 54.4/316 MINTZ, LEVIN, COHN, FERRIS, GLOVSKY (57) ABSTRACT AND POPEO, PC 5 Palo Alto Square - 6th Floor,3000 El Camino Real A method for modulating at least one pharmacokinetic prop PALO ALTO, CA 94306-2155 (US) erty of a protease inhibitor upon administration to a host is provided. One administers to the host an effective amount of a bifunctional compound of less than about 5000 daltons (21) Appl. No.: 12/151,329 comprising the protease inhibitor or an active derivative thereof and a pharmacokinetic modulating moiety. The phar (22) Filed: May 5, 2008 macokinetic modulating moiety binds to at least one intrac ellular protein. The bifunctional compound has at least one (30) Foreign Application Priority Data modulated pharmacokinetic property upon administration to the hostas compared to a free drug control that comprises the Nov. 6, 2006 (US) ................. PCT/US2006/043400 protease inhibitor. FKBP-binding FKBP-binding interface interface Conjugate Target Binding Calcineurin-binding interface Patent Application Publication Dec. 11, 2008 Sheet 1 of 11 US 2008/0306.098 A1 O) \iO Ol cy A- S' O I N CD (5. 8. (5 sc T O W I G CO O O M I CS O O CO y ? H Patent Application Publication Dec. 11, 2008 Sheet 2 of 11 US 2008/0306.098 A1 g Patent Application Publication Dec. 11, 2008 Sheet 3 of 11 US 2008/0306.098 A1 Patent Application Publication Dec. 11, 2008 Sheet 4 of 11 US 2008/0306.098 A1 Patent Application Publication Dec. 11, 2008 Sheet 5 of 11 US 2008/0306098A1 +dg>{-Wri| m?gOunoW WrigOuno ,|X-3-OJn0Wrig 91 (uu GS) 8380Sejon Patent Application Publication Dec. 11, 2008 Sheet 6 of 11 US 2008/0306.098 A1 Ex s & . Patent Application Publication Dec. 11, 2008 Sheet 7 of 11 US 2008/0306.098 A1 2 2 O Patent Application Publication Dec. 11, 2008 Sheet 8 of 11 US 2008/0306.098 A1 2Y .9g a ...g 5,O CD S 5 1- T - l O O O O O O I 8 O CD O O CO - CD -N4 9. s-d - 5 O O O O f 5. 5. 5. f Patent Application Publication Dec. 11, 2008 Sheet 9 of 11 US 2008/0306.098 A1 ?ONNoSS HO 2 Patent Application Publication Dec. 11, 2008 Sheet 10 of 11 US 2008/0306.098 A1 `oog HOSHNIOGE Patent Application Publication Dec. 11, 2008 Sheet 11 of 11 US 2008/0306.098 A1 OH ‘OCIE SHN -?-------------- SHN/OCJE ?HN ò US 2008/0306098 A1 Dec. 11, 2008 PHARMACOKINETCS OF PROTEASE administers to the host an effective amount of a bifunctional INHIBITORS AND OTHER DRUGS compound of less than about 5000 daltons comprising the protease inhibitor or an active derivative thereof and a phar CROSS-REFERENCE TO RELATED macokinetic modulating moiety. The pharmacokinetic modu APPLICATIONS lating moiety binds to at least one intracellular protein. The 0001. This application claims priority to PCT/US2006/ bifunctional compound has at least one modulated pharma 043400 filed Nov. 6, 2006, which claims priority to U.S. cokinetic property upon administration to the host as com provisional application Ser. No. 60/734,197, filed Nov. 5, pared to a free drug control that comprises the protease inhibi 2005. Both priority documents are incorporated by reference tOr. 0009. In a further embodiment of this invention, a bifunc in their entireties. tional compound comprising protease inhibitor functionality TECHNICAL FIELD and a pharmacokinetic modulating moiety are provided. 0010. In a further aspect of the invention, a bifunctional 0002 This invention relates generally to pharmacology compound is provided in a pharmaceutical formulation which and more specifically to the modification of known active is designed to have a controlled release mechanism in addi agents to give them more desirable properties. tion to that provided by the bifunctional compound. The bifunctional compound may comprise a drug moiety that is a BACKGROUND ART protease inhibitor or some other drug. 0003. When HIV was first discovered, it was feared that all persons infected with HIV would eventually develop full BRIEF DESCRIPTION OF THE DRAWINGS blown AIDS. However, drugs were developed and approved (0011 FIG. 1A depicts the structure of FK506 linked to a which could slow the proliferation of the HIV virus. The most modular linker and target binding moiety, for example a pro usual therapies over the last decade for HIV-infected people tease inhibitor. Due to the modular nature of the synthesis, the have been three-drug cocktails, in which one of the drugs is an linker group and target-binding group have been altered. FIG. HIV protease inhibitor and the other two are reverse-tran 1B illustrates how the steric bulk of an FKBP protein can scriptase inhibitors. The introduction of three-drug cocktails confer protection from P450 enzymes. in the mid-1990s has allowed many HIV-infected people to survive for long periods of time without developing AIDS and 0012. In FIG. 2, the left side depicts the bimodal binding has allowed some AIDS patients to experience a notable character of FK506 whereby it binds both FKBP and cal remission. cineurin. The schematic on the right depicts how the cal 0004 Patient compliance and drug toxicity have always cineurin-binding mode can be eliminated by Substituting a been major issues with HIV protease inhibitors due to the linker and target binding moiety. In this manner, FK506 can frequency of dosage and co-administration of other HIV simultaneously target FKBP and bind a second protein. therapeutics. A reduction in dosage frequency would repre (0013. In FIG. 3, (A) shows the structure of FK506 bound sent an improvement in quality of life for the patient and a to curcumin. (B) illustrates that FK506-curcumin is protected lower chance of toxic side effects due to decreased production from CYP3a4, a P450 enzyme, in the presence of FKBP. (C) of secondary metabolites, especially in the liver. Although gives a schematic of the Invitrogen assay used. recent HIV protease inhibitors require a reduced dosage bur 0014. In FIG. 4, the left side illustrates an exemplary syn den compared with earlier drugs, there is still significant thetic scheme for bifunctional compounds of the invention. opportunity for improving PIs by reducing first pass clear The right side shows the application of this scheme to ance via cytochrome P450 enzymes and increasing the drug amprenavir, lopinavir, and ritonavir. half-life in the circulation. 0015 FIG. 5 depicts useful linkers which have amine and 0005 Examples of HIV protease inhibitors which have (alkyl-protected) carboxyl moieties. diminished half lives due to poor pharmacokinetics are 0016 FIG. 6 sets out a synthetic scheme for the synthesis amprenavir, lopinavir, indinavir and ritonavir, among others. of an amprenavir-based SLF-PI conjugate. The amprenavir 0006 Previous methods to improve pharmacokinetics like moiety is shown at the right in FIG. 6. (PK) of HIV protease inhibitors include: medicinal chemis (0017 FIGS. 7A-7B depict a reaction schema for ritonavir try-based analog synthesis, employing pro-drug strategies, and lopinavir respectively. Note the schema proceeds via improved formulation, and co-administration with P450 and analogous chemistry using the well-characterized Boc (t-bu P-glycoprotein inhibitors. Regardless of the methods toxycarbonyl) leaving group. employed, these approaches share a desired outcome: improve pharmacokinetics to make treatment easier for DETAILED DESCRIPTION OF PREFERRED patients. However, these methods have not yielded an inhibi EMBODIMENTS tor that requires a Substantially lower dose (e.g., once or twice 0018. Before describing the present invention in detail, it per week) over the prior inhibitors and is relatively non-toxic is to be understood that this invention is not limited to specific compared with prior inhibitors. Solvents, materials, or device structures, as Such may vary. It 0007. There is therefore still a need in the art for protease is also to be understood that the terminology used herein is for inhibitors and associated dosage forms which have reduced the purpose of describing particular embodiments only, and is first pass clearance and/or improved pharmacokinetics. not intended to be limiting. 0019. As used in this specification and the appended DISCLOSURE OF THE INVENTION claims, the singular forms “a,” “an and “the include both 0008. In an embodiment of this invention, a method for singular and plural referents unless the context clearly dic modulating at least one pharmacokinetic property of a pro tates otherwise. Thus, for example, reference to “an active tease inhibitor upon administration to a host is provided. One ingredient' includes a plurality of active ingredients as well US 2008/0306098 A1 Dec. 11, 2008 as a single active ingredient, reference to “a temperature' bifunctional compound has at least one modulated pharma includes a plurality oftemperatures as well as single tempera cokinetic property upon administration to the host as com ture, and the like. pared to a free drug control that comprises the protease inhibi 0020. The term “bifunctional compound” refers to a non tOr. naturally occurring compound that includes a pharmacoki 0033 Bifunctional compound in general have aroused netic modulating moiety and a drug moiety, where these two considerable interest in recent years.