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(12) Patent Application Publication (10) Pub. No.: US 2006/0154991 A1 Johnson Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0154991 A1 Johnson Et Al US 2006O154991A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0154991 A1 Johnson et al. (43) Pub. Date: Jul. 13, 2006 (54) INHIBITORS OF CANDIDA ALBICANS Related U.S. Application Data (75) Inventors: Douglas I Johnson, Essex Junction, VT (60) Provisional application No. 60/445,314, filed on Feb. (US); Kurt A. Toenjes, Burlington, VT 5, 2003. (US) Publication Classification Correspondence Address: WOLF GREENFIELD & SACKS, PC (51) Int. Cl. NULL A6II 3L/38 (2006.01) FEDERAL RESERVE PLAZA (52) U.S. Cl. .............................................................. 514/649 6OO ATLANTIC AVENUE BOSTON, MA 02210-2206 (US) (57) ABSTRACT (73) Assignee: University of Vermont and State Agri The invention provides methods for identifying modulators cultural College, Burlington, VT (US) of yeast phenotypic transitions and methods for treating fungal infections with modulators of phenotypic transitions (21) Appl. No.: 10/544,691 of yeast cells. These methods include methods for identify ing inhibitors of the budded-to-hyphal transition of Candida (22) PCT Filed: Feb. 5, 2004 albicans and methods for treating fungal infections with inhibitors of the budded-to-hyphal transition of Candida (86). PCT No.: PCT/USO4/O3208 albicans. Patent Application Publication Jul. 13, 2006 Sheet 1 of 3 US 2006/0154991 A1 Figure 1. The budded or yeast-like (A), pseudohyphal (B), and hyphal growth forms are inter-convertible and differ in growth properties and cell cycle regulation. Adapted from (12, 15)} Patent Application Publication Jul. 13, 2006 Sheet 2 of 3 US 2006/0154991 A1 Figure 2. Signals (pH, temp., serum, maerophages) Cdc24 (Cdc24)2- s- N.Go (Gpx2) clad (CL5 Catzoste20) Cyr1 Stei (Stel) cAMP signal Est7 (Stet) Cek (Kiss) protein kinase A Cphi (Stel2) Efg1 (Phd) Adapted transvaarov, Eads in Microbiology 7333-338 999 Patent Application Publication Jul. 13, 2006 Sheet 3 of 3 US 2006/0154991 A1 Figure 3. esults from ...S. f6 C. albicans cells were incubated in YNB media to promote budded growth and then transferred to Spider media to induce the budded-to-hyphal transition and hyphal elongation. The indicated small molecules were added at the indicated concentrations at time 0 and growth was allowed to continue for 4 h at 37'C before the cells were fixed and observed microscopically. US 2006/0154991 A1 Jul. 13, 2006 INHIBITORS OF CANDDA ALBCANS 6, or 7-membered ring; m is an integer varying from 0 to 5: and n is an integer varying from 0 to 5; in an effective FIELD OF THE INVENTION amount. 0001. The invention relates to methods for identifying 0007) In some embodiments, the compound is of the modulators of yeast phenotypic transitions, including meth formula: ods for identifying inhibitors of the budded-to-hyphal tran sition of Candida albicans. The invention also relates to treating fungal infections with modulators of phenotypic RI transitions of yeast cells, including inhibitors of the budded M to-hyphal transition of Candida albicans. s1 (CRR)-N R5 R2 BACKGROUND OF THE INVENTION N N 0002 Candida albicans is the most common and possi X, it --Y bly the most important causative agent of human fungal 2 21 infections (Edmond, M. B., et al. 1999, Clin. Infect. Dis. 29:239-244). Candida albicans, (C. albicans) is a major opportunistic pathogen of immunocompromised hosts, wherein R', R. R. R. R. X., and Y are as defined above including AIDS patients and patients undergoing chemo for Formula 1. In other embodiments, the compound is of the therapy, patients who have had tissue transplants, and formula: patients with central venous catheters. Studies indicate that up to ninety percent of AIDS patients suffer from oropha ryngeal and esophageal candidiasis, in which C. albicans is R1 the major causative agent (Schmidt-Westhausen, A., et al., A 1991, J. Oral Pathol. Med. 20:467-472). 1N1N 2 R5 R SUMMARY OF THE INVENTION N N 0003) The invention is based, in part, on the discovery of Xin it --Y, a method of identifying inhibitors of the budded-to-hyphal 2 21 transition of yeast cells, and the use of the inhibitors to treat fungal infections. Previously, most, if not all, antifungal agents killed yeast cells, and often were toxic to the host wherein R. R. R. X., and Y are as described above for (patient) cells as well. Formula 1. In yet other embodiments, the compound has the formula: 0004 The present invention includes methods for treat ing fungal infections by administering a compound that modulates phenotypic transitions of yeast cells. 0005 According to one aspect of the invention, methods s1N1 /\ for treating fungal infections by administering a compound of Formula I: R1 M -(CR'R')-N S R2 0008. In some embodiments, the compounds above are R5 provided as a mixture of isomers, which may include N N diastereomers or enantiomers. In other embodiments, the Xin --Y compound is greater than 60%, 70%, 80%, 90%, 95% or 2 21 99% of one isomer. 0009. In another aspect of the invention, methods for 0006 or a pharmaceutically acceptable salt thereof, are treating a fungal infection by administering a compound of provided, wherein R' and R are independently selected Formula II: from the group consisting of hydrogen, C-C alkyl, C-C, alkenyl, C-C alkynyl, aryl, and heteroaryl; R. R. and R' are independently selected from the group consisting of hydrogen, hydroxy, halo, C-C alkoxy, C-C alkyl, C-C, alkenyl, and C-C alkynyl; P is an integer varying from 1 x-S \ sy, to 5; each X and each Y are independently selected from the group consisting of halo, hydroxy, C-C alkoxy, nitro, C-C alkyl, C-C alkenyl, C-C alkynyl, amido, aryl, or a pharmaceutically acceptable salt thereof, are provided heteroaryl, and acyl: or two Xs or two Ys together form a 5. wherein R' and R are independently selected from the US 2006/0154991 A1 Jul. 13, 2006 group consisting of hydrogen, C-C alkyl, C-C alkoxy, In another embodiment, the compound has the formula: hydroxy, and halo; p is an integer ranging from 1 to 5; each X and each Y are independently selected from the group OH consisting of halo, hydroxy, nitro, C-C alkoxy, C-C, alkyl, C-C alkenyl, C-C alkynyl, amido, aryl, heteroaryl, N-- and acyl: or two Xs or two Ys together form a 5, 6, or 7-membered ring; m is an integer varying from 0 to 11; and n is an integer varying from 0 to 11 in an effective amount. 0010) In some embodiments, the compound is of the 0014. In some embodiments, the compounds above are formula: provided as a mixture of isomers, which may include diastereomers or enantiomers. In other embodiments, the compound is greater than 60%, 70%, 80%, 90%, 95% or 99% of one isomer. 0015. In another aspect of the invention, methods for xx()--ice- \ Sy) treating fungal infections comprising administering a com pound of Formula III: 0011 wherein R', R, X, Y are as defined above for Formula II. In some embodiments, m is an integer greater than or equal to 2. In some embodiments, the compound is of the formula: or a pharmaceutically acceptable salt thereof, are provided, wherein R' and R are independently selected from the group consisting of hydrogen, C-C alkyl, C-C alkenyl, C-C alkynyl, aryl, and heteroaryl; wherein R. R. R. R. and Rare independently selected from the group consisting of hydrogen, hydroxy, C-C alkoxy, halo, C-C alkyl, 0012 wherein R', Y, and Y are as defined above for C-C alkenyl, and C-C alkynyl; or RandR together are Formula II. In other embodiments, the compound is of the a carbonyl oxygen; n is an integer ranging from 1 to 5; each formula: X and each Y are independently selected from the group consisting of halo, hydroxy, C-C alkoxy, nitro, C-C, alkyl, C-C alkenyl, C-C alkynyl, amido, aryl, heteroaryl, and acyl: or two Xs or two Ys together form a 5, 6, or 7-membered ring; m is an integer varying from 0 to 5; and p is an integer varying from 0 to 5 in an effective amount. 0016. In some embodiments, n is 1 or 2. In another embodiment, n is 3. In yet other embodiments, n is 4 or 5. In some embodiments, m and p are each 0, that is the aryl rings are not substituted. In other embodiments, one or both of the aryl rings may be substituted. 0013 wherein X, and Y are as described above for 0017. In some embodiments, R and R together are a Formula II. In certain embodiments, X and Y are each C-C, carbonyl oxygen. In some of these embodiments, the com alkyl. In one embodiment, the compound has the formula: pounds are of the formula: US 2006/0154991 A1 Jul. 13, 2006 0.018 wherein R. R. R. X., and Y are as described 0022. In some embodiments, R is hydrogen. In other above for Formula III. embodiments, R is not hydrogen, and the compounds may exist only in the E or Z configuration, or a mixture thereof. 0019. In some embodiments, R is C-C alkoxy and R' In other embodiments, each X and each Y are selected from and R are each alkyl. In some of these embodiments, the C-C alkoxy and hydroxy. In some embodiments, n is 0. In compound is of the formula: other embodiments, n is 1, 2, 3, 4, or 5. 0023. In still other embodiments, m is 0. In other embodi ments, m is 1. In still other embodiments, m is 2, 3, 4, or 5.
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