WO2021001697A1 - Novel boronic acid containing peptidomimetics as malarial serine protease inhibitors - Google Patents
Novel boronic acid containing peptidomimetics as malarial serine protease inhibitors Download PDFInfo
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- WO2021001697A1 WO2021001697A1 PCT/IB2020/053392 IB2020053392W WO2021001697A1 WO 2021001697 A1 WO2021001697 A1 WO 2021001697A1 IB 2020053392 W IB2020053392 W IB 2020053392W WO 2021001697 A1 WO2021001697 A1 WO 2021001697A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to medicine, and in particular to the treatment of malarial infections, more particularly to inhibitors of malarial serine proteases. Even more particularly, the invention relates to novel boronic acid containing peptidomimetics and pharmaceutical compositions thereof and their use as inhibitors for subtilisin-like serine proteases (SUB).
- SUB subtilisin-like serine proteases
- subtilisin-like serine proteases have been recognized as promising molecular targets for new drug development (Withers-Martinez, C.; Suarez, C.; Fulle, S.; Kher, S.; Penzo, M.; Ebejer, J.-P.; Koussis, K.; Hackett, F.; Jirgensons, A.; Finn, P.; Blackman, M. J. Plasmodium subtilisin- like protease 1 (SUB1): Insights into the active-site structure, specificity and function of a pan-malaria drug target.
- SUB1 subtilisin-like serine proteases
- the invention features a method of treating malarial infections in humans or animals, comprising administering to a human or animal in need of a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of subtilisin-like serine protease (SUB).
- a compound or prodrug thereof or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of subtilisin-like serine protease (SUB).
- SUV subtilisin-like serine protease
- the invention features a pharmaceutical composition for treatment of malaria infections comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of subtilisin-like serine proteases (SUB).
- a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of subtilisin-like serine proteases (SUB).
- SUB subtilisin-like serine proteases
- the invention features the use of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of subtilisin-like serine proteases (SUB), in the manufacture of a medicament for treatment or prevention of malaria infections.
- SUB subtilisin-like serine proteases
- the invention features a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug for use in treating or preventing malaria infections, wherein the compound is an inhibitor of subtilisin-like serine proteases (SUB).
- SUB subtilisin-like serine proteases
- the inhibitor of subtilisin-like serine proteases is a compound of Formula I, generally referred herein as boronic acid containing peptidomimetic: [11] wherein:
- R 4 is H or Me
- R 3 is H, C 1-6 alkyl, cycloC 3-12 alkyl, cycloC 3-12 alkyl-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, biaryl, arylC 1-6 alkyl, arylC 2-6 alkenyl, arylC 2-6 alkynyl, heteroaryl, heteroarylC 1-6 alkyl, heteroarylC 2-6 alkenyl,
- R 12 and R 13 are independently H, C 1-6 alkyl, cycloC 3-12 alkyl, cycloC 3-12 alkyl-C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, biaryl, arylC 1-6 alkyl, arylC 2-6 alkenyl, arylC 2-6 alkynyl, heteroaryl, heteroarylC 1-6 alkyl, heteroarylC 2-6 alkenyl
- n is an integer selected from 1 to 6;
- R 2 , R 5 ,R 6 , R 7 , R 8 , R 9 , R 10 , R 11 are independently
- L represents -W-X-Y-Z-; or -W-X-Y, or or -W-X R 1 and R 2
- R 10 and R 11 taken together represent -W-X-Y-Z-, or -W-X-Y-, or -W-X- or
- W represents a single bond, oxygen, sulfur, -NR 14 or–CR 14 R 15 ,
- X represents oxygen, sulfur, -NR 14 or–C(R 14 )R 15 ,
- Y represents oxygen, sulfur, -NR 14 or–C(R 14 )R 15 ,
- R 14 and R 15 are independently H, C 1-6 alkyl, cycloC 3-12 alkyl, cycloC 3-12 alkyl-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, biaryl, arylC 1-6 alkyl, arylC 2-6 alkenyl, arylC 2-6 alkynyl, heteroaryl, heteroarylC 1-6 alkyl, heteroarylC 2-6 alkenyl, heteroarylthio, 2,3-dihydro-1H-indenyl, C 1-6 alkoxyC 1-6 alkyl, aryloxyarylC 1-6 alkoxy, C 1-6 alkylthio, C 4-6 alkenylthio, cycloC 3-12 alkylthio, cycloC 3-12 alkyl-C 1-6 alkylthio, cycloC 3-12 alkyl-C 1-6 alkylthio, cycloC 3-12 al
- the treatment is treatment of a disease or disorder that is mediated by a malarial serine protease or human serine proteases.
- the treatment is treatment of a disease or disorder that is ameliorated by the inhibition of a malarial serine protease or human serine protease.
- the treatment is treatment of a disease or disorder that is treated by a malarial serine protease or human serine protease inhibitor; pharmaceutical composition intended for parenteral or peroral administration to humans.
- the invention features a kit comprising a boronic acid containing peptidomimetic as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging.
- the invention features compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
- the invention features compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
- the invention features novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
- the invention features the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
- Subtilisin-like serine (SUB) proteases are malarial serine proteases which have been identified as a group of promising biological targets for the development of new anti-malarial agents as these are involved in parasite egress from infected erythrocytes (Withers-Martinez, C.; Suarez, C.; Fulle, S.; Kher, S.; Penzo, M.; Ebejer, J.-P.; Koussis, K.;98ett, F.; Jirgensons, A.; Finn, P.; Blackman, M. J.
- Plasmodium subtilisin-like protease 1 (SUB1): Insights into the active-site structure, specificity and function of a pan-malaria drug target. International Journal for Parasitology 2012, 42, 597-612. Kher, S. S.; Penzo, M.; Fulle, S.; Finn, P. W. ; Blackman, M. J.; Jirgensons, A. Substrate derived peptidic a-ketoamides as inhibitors of the malarial protease PfSUB1. Bioorg. Med. Chem.
- P. falciparum SUB1 (PfSUB1) was produced and purified as previously described (C. Withers-Martinez, C. Suarez, S. Fulle, S. Kher, M. Penzo, J. P. Ebejer, K. Koussis, F. hackett, A. Jirgensons, P. Finn, M. J. Blackman, International Journal for Parasitology; 2012, 42, 597).
- the enzyme was diluted in digestion buffer (25 mM CHAPS, 12 mM CaCl2, 25 mM Tris-HCl, pH 8.2) and dispensed into a white flat-bottomed 96-well fluorescence microtitre plates (Nunc).
- Test compounds were solubilized in dimethyl sulfoxide (DMSO), serially diluted and added at 2 % to the well.
- DMSO dimethyl sulfoxide
- the rhodamine-labelled fluorogenic substrate SERA4st1F-6R12 was added at a final concentration of 0.1 ⁇ M in a final volume of 100 ⁇ l and the rate of hydrolysis was monitored with a Cary Eclipse spectrofluorimeter (Varian, UK) as previously described. Excitation and emission wavelengths used were 552 nm and 580 nm respectively.
- Plasmodium falciparum (clone 3D7) was assessed using a SYBR Green I assay. Test compounds (dissolved in DMSO at concentrations ranging from 1 mM–0.1 uM) were added in triplicate to wells of flat bottomed, 96 well microtitre plates (1 ⁇ L per well). Wells were then supplemented with 100 ⁇ L per well of a synchronous P. falciparum parasite culture at 0.1 % parasitaemia, 1 % haematocrit.
- Each assay plate also included DMSO only control wells, as well as additional control wells containing uninfected erythrocytes only. Plates were incubated in sealed humidified gassed chambers at 37 o C for 96 h to allow the parasites to undergo two entire cycles of erythrocytic growth. Wells were then supplemented with 100 ⁇ L of a 1:5,000 dilution of stock SYBR Green I (Life Technologies, catalogue #S7563) diluted in 20 mM Tris-HCl pH 7.5, 5 mM EDTA, 0.008 % (w/v) saponin, 0.08 % (v/v) Triton X100.
Abstract
The invention relates to novel boric acid-containing peptidomimetics I, (I) acting as inhibitors of the malaria subtilisin-related serine protease (SUB). They are useful as medicinal preparations or as ingredients for the treatment of malaria.
Description
NOVEL BORONIC ACID CONTAINING PEPTIDOMIMETICS AS MALARIAL SERINE
PROTEASE INHIBITORS Field of invention
[1] The present invention relates to medicine, and in particular to the treatment of malarial infections, more particularly to inhibitors of malarial serine proteases. Even more particularly, the invention relates to novel boronic acid containing peptidomimetics and pharmaceutical compositions thereof and their use as inhibitors for subtilisin-like serine proteases (SUB). Background of invention [2] Widespread resistance to practically all currently used drugs has stimulated the search for antimalarials with novel mechanisms of action (Hyde, J. E. Drug-resistant malaria - an insight. FEBS J. 2007, 274, 4688-4698; Choi, S. R.; Mukherjee, P.; Avery, M. A. The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr. Med. Chem. 2008, 15, 161-171; Wells, T. N.; Alonso, P. L.; Gutteridge, W. E. New medicines to improve control and contribute to the eradication of malaria. Nat. Rev. Drug Discov. 2009, 8, 879-891). Resistance to current anti-malarial agents in malaria-endemic regions continues to spread, indicating that current therapeutic agents will be practically ineffective in the near future. A precondition for the development of antimalarial agents is inhibition of the malaria parasite life cycle through a mechanism that differs from the mode of action of currently used therapeutic agents (N. K. Sahu, S. Sahu and D. V. Kohli, Novel Molecular Targets for Antimalarial Drug. Chem. Biol. Drug. Des., 2008, 71, 287–297)
[3] This could be achieved by targeting functional malarial proteins involved in the blood stage of the parasite life cycle. Malarial enzymes such as subtilisin-like serine proteases (SUB) have been recognized as promising molecular targets for new drug development (Withers-Martinez, C.; Suarez, C.; Fulle, S.; Kher, S.; Penzo, M.; Ebejer, J.-P.; Koussis, K.; Hackett, F.; Jirgensons, A.; Finn, P.; Blackman, M. J. Plasmodium subtilisin- like protease 1 (SUB1): Insights into the active-site structure, specificity and function of a pan-malaria drug target. International Journal for Parasitology 2012, 42, 597-612. Thomas, J. A.; Tan, M.S.Y; Bisson, C.; Borg, A.; Umrekar T. R; Hackett F, Hale VL, Vizcay-Barrena G, Fleck RA, Snijders AP, Saibil HR, Blackman MJ. A protease cascade regulates release of
the human malaria parasite Plasmodium falciparum from host red blood cells. Nat Microbiol. 2018, 3(4),447-455).
[4] Several inhibitors for SUB subtype PfSUB1 have been developed (Kher, S. S.; Penzo, M.; Fulle, S.; Finn, P. W. ; Blackman, M. J.; Jirgensons, A. Substrate derived peptidic a-ketoamides as inhibitors of the malarial protease PfSUB1.Bioorg. Med. Chem. Lett., 2014, 24(18), 4486-4489), however, so far none of them have advanced to clinical trial. Summary of the invention
[5] In a first aspect, the invention features a method of treating malarial infections in humans or animals, comprising administering to a human or animal in need of a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of subtilisin-like serine protease (SUB).
[6] In another aspect, the invention features a pharmaceutical composition for treatment of malaria infections comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of subtilisin-like serine proteases (SUB).
[7] In another aspect, the invention features the use of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of subtilisin-like serine proteases (SUB), in the manufacture of a medicament for treatment or prevention of malaria infections.
[8] In another aspect, the invention features a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug for use in treating or preventing malaria infections, wherein the compound is an inhibitor of subtilisin-like serine proteases (SUB).
[9] In one embodiment the inhibitor of subtilisin-like serine proteases (SUB) is a compound of Formula I, generally referred herein as boronic acid containing peptidomimetic:
[11] wherein:
[12] R4 is H or Me;
[13] R3 is H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl,
R12O(CH2)n, R12S(CH2)n, R12OC(=O)(CH2)n, R12N(R13)C(=O)(CH2)n, R12N (R13)(CH2)n, Wherein R12 and R13 are independently H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl
[14] n is an integer selected from 1 to 6;
[15] R1
, R2, R5,R6, R7, R8, R9, R10, R11 are independently
-H, -F, -Cl, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-O-L-OH, -OR14,
-O-L-NH2, -O-L-NHR14, -O-L-NR14
2, -O-L-R14NR15, -L-OR14,-O-L-OR14,-OCF3, -OCH2CF3, -OCF2CF2H, -L-OR14,-O-L-OR14,-OCF3, -OCH2CF3, -OCF2CF2H, SR14, SCF3, - CN, -NO2, -NO2, -NH2, -NHR14, -NR14
2, -N(R14)R15,
-L-NH2, -L-NHR14, -L-NR14
2, -L-N(R14) R15,-NH-L-NH2, -NH-L-NHR14,
-NH-L-NR14
2, -NH-L-N(R14)R15,
-NR14-L-NH2, -NR14-L-NHR14, -NR14-L-NR14
2, -NR14-L-N(R14)R15,
L-N(R14)R15,
-C(=O)OH, -C(=O)OR14, -C(=O)NH2, -C(=O)NHR14, -C(=O)NR14
2,
-C(=O)N(R14)R15,-NHC(=O)R14, -NR14C(=O)R15, -NHC(=O)OR14,
-NR14C(=O)OR15, -OC(=O)NH2, -OC(=O)NHR14, -OC(=O)NR14
2,
-OC(=O) R14NR15,-OC(=O)R14, -C(=O)R13,-NHC(=O)NH2, -NHC(=O)NHR14,
-NHC(=O)NR14
2, -NHC(=O)N(R14)R15, -NR14C(=O)NH2, -N(R14)C(=O)NHR15,
-NR14C(=O)NR14
2, -NR14C(=O)N
-NHS(=O)2R14, -N(R14)S(=O)2R15,-S(=O)2NH2, -S(=O)2NHR14, -S(=O)2NR14
2,
-S(=O)2N(R14)R15,-S(=O)R14, -S(=O)2R14,-OS(=O)2R14,-S(=O)2OR14,
[16] C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, heteroarylthio, 2,3-dihydro-1H-indenyl, 2-indanylamino,
tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C1-6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3- dihydro-2H-isoindol-2-yl;
or R5
, R7, R8, are independently =O,=NR14,=NOH, or =NOR14;
[17] L represents -W-X-Y-Z-; or -W-X-Y, or or -W-X R1 and R2
or R1 and R3
or R5 and R6
or R7 and R8
or R7 and R11
or R8 and R9
or R9 and R10
or R10 and R11 taken together represent -W-X-Y-Z-, or -W-X-Y-, or -W-X- or
wherein
W represents a single bond, oxygen, sulfur, -NR14 or–CR14R15,
X represents oxygen, sulfur, -NR14 or–C(R14)R15,
Y represents oxygen, sulfur, -NR14 or–C(R14)R15,
Z represents oxygen, sulfur, -NR14 or–C(R14)R15; [18] R14 and R15 are independently H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, heteroarylthio, 2,3-dihydro-1H-indenyl, C1-6alkoxyC1-6alkyl, aryloxyarylC1-6alkoxy, C1-6alkylthio, C4-6alkenylthio, cycloC3-12alkylthio, cycloC3-12alkyl-C1-6alkylthio, cycloC3-12alkyl-C3-6alkenylthio, C1-6alkoxyC1-6alkylthio, C1- 6alkoxyC3-6alkenylthio, arylC3-6alkenylthio, heteroarylC1-6alkylthio, C1-6alkylsulfonyl, cycloC3-12alkyl-C1-6alkylsulfonyl, arylC1-6alkylsulfonyl, C1-6alkylamino, di-C1-6alkylamino, cycloC3-12alkylamino, C1-C6alkoxy-cycloC3-C12alkylamino, cycloC3-12alkyl-C1-6alkylamino, di-C1-6alkylaminoC1-6alkyl, C1-6alkoxy-C2-6alkylamino, arylamino, arylC1-6alkylamino, N- cycloC3-12alkyl-N-C1-6alkylamino, N-aryl-N-C1-6alkylamino, N-arylC1-6alkyl-N-C1-
6alkylamino, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4- heteroarylpiperidino, morpholino, piperazino, 4-C1-6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, heteroarylC1-6alkoxy, heteroarylamino, or heteroarylC1-6alkylamino; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[19] In one embodiment, the treatment is treatment of a disease or disorder that is mediated by a malarial serine protease or human serine proteases.
[20] In one embodiment, the treatment is treatment of a disease or disorder that is ameliorated by the inhibition of a malarial serine protease or human serine protease.
[21] In one embodiment, the treatment is treatment of a disease or disorder that is treated by a malarial serine protease or human serine protease inhibitor; pharmaceutical composition intended for parenteral or peroral administration to humans.
[22] In another aspect, the invention features a kit comprising a boronic acid containing peptidomimetic as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging.
[23] In another aspect, the invention features compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
[24] In another aspect, the invention features compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
[25] In another aspect, the invention features novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
[26] In another aspect, the invention features the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
[27] As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention. Description of invention
[28] Subtilisin-like serine (SUB) proteases are malarial serine proteases which have been identified as a group of promising biological targets for the development of new anti-malarial agents as these are involved in parasite egress from infected erythrocytes (Withers-Martinez, C.; Suarez, C.; Fulle, S.; Kher, S.; Penzo, M.; Ebejer, J.-P.; Koussis, K.; Hackett, F.; Jirgensons, A.; Finn, P.; Blackman, M. J. Plasmodium subtilisin-like protease 1 (SUB1):
Insights into the active-site structure, specificity and function of a pan-malaria drug target. International Journal for Parasitology 2012, 42, 597-612. Kher, S. S.; Penzo, M.; Fulle, S.; Finn, P. W. ; Blackman, M. J.; Jirgensons, A. Substrate derived peptidic a-ketoamides as inhibitors of the malarial protease PfSUB1. Bioorg. Med. Chem. Lett., 2014, 24(18), 4486- 4489; Thomas JA, Tan MSY, Bisson C, Borg A, Umrekar TR, Hackett F, Hale VL, Vizcay- Barrena G, Fleck RA, Snijders AP, Saibil HR, Blackman MJ. A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells. Nat Microbiol.2018, 3(4), 447-455).
[29] When testing the novel boronic acid containing peptidomimetic derivatives for their ability to inhibit SUB we have unexpectedly discovered, that said derivatives exhibit pronounced inhibitory properties toward said serine proteases and inhibition of parasite growth in red cells, and thus are useful in treatment of malaria.
[30] According to this invention, the results from SUB inhibition studies demonstrate that boronic acid containing peptidomimetic derivatives are novel class inhibitors of serine proteases. Several example compounds from the present invention display nanomolar to low micromolecular inhibitory potency.
Stereochemistry
[31] Many of the chemical structures shown herein indicate one or more specific stereoisomeric configurations. Similarly, many of the chemical structures shown herein are silent in this respect, and do not indicate any stereoisomeric configuration. Similarly, many of the chemical structures shown herein indicate the specific stereoisomeric configurations at one or more positions, but are silent with respect to one or more other positions. Where a chemical structure herein is silent with respect to the stereoisomeric configuration at a position, that structure is intended to depict all possible stereoisomeric configurations at that position, both individually, as if each possible stereoisomeric configuration was individually recited, and also as a mixture (e.g., a racemic mixture) of stereoisomers.
Combinations
[32] Each and every compatible combination of the embodiments described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited. Examples of Specific Embodiments
[33] The following examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way.
[34] The following boronic acid containing peptidomimetic derivatives 9.1, 10.2-10.8 and 11.1-11.8 were prepared as examples of the current invention:
[35] Boronic acid derivatives 9-11 were prepared according to scheme 1. Coupling of amino acid derivatives 1 and 2 provided protected dipeptide 3. This was N-deprotected and subjected to coupling with amino acid 4 leading to protected tri-peptide 5. This was N- deprotected and modified at the nitrogen to give intermediate 6. O-deprotection gave acid 7 which was coupled with aminoboronic acid derivative 8. The resulting intermediate 9 was subjected to the cleavage of boronic ester and amino acid side chain protection leading to products 10 and 11.
Scheme 1
Synthesis of intermediates 3, general method A
[36] Exemplified by the synthesis of 3.1:
[37] A mixture of glycine methyl ester hydrochloride (2.1) (401 mg, 3.2 mmol), Fmoc- Thr(tBu)-OH 1.1 (1.30 g, 3.2 mmol, 1 eq.), HATU (1.34 g, 3.5 mmol, 1.1 eq.) and DIPEA (1.66 mL, 9.6 mmol, 3 eq.) in DCM (40 mL) was stirred for 2 h at room temperature. The reaction mixture was washed with H2O (2x20 mL) and then with brine (20 mL). Organic phase was dried over Na2SO4, organic phase was evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane: EtOAc, 4:1 - 1:1 (Rf=~0.5, when Hex:EtOAc 2:1) to provide 3.1 (1.37 g, 92 %) as a solid compound.
[38] 1H NMR (400 MHz, Chloroform-d) d 7.76 (d, J = 7.4 Hz, 2H), 7.68– 7.57 (m, 3H), 7.40 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 6.00 (d, J = 4.9 Hz, 1H), 4.45– 4.34 (m, 2H), 4.28– 4.16 (m, 3H), 4.16– 4.00 (m, 2H), 3.78 (s, 3H), 1.31 (s, 9H), 1.09 (d, J = 6.4 Hz, 3H).
13C NMR (101 MHz, Chloroform-d) d 170.0, 169.8, 156.1, 144.0, 143.8, 141.45, 141.43, 127.8, 127.2, 125.3, 120.12, 120.10, 75.8, 67.1, 66.7, 58.7, 52.5, 47.3, 41.5, 28.3, 16.9.
HR-MS (ESI/TOF) calcd for C26H33N2O6 [M+H]+ 469.2339, found 469.2337. [39] By a method analogous to Method A, the following compounds were obtained:
[40] Exemplified by the synthesis of 5.1:
[41] A mixture of 3.1 (279 mg, 0.60 mmol) in DMF (4 mL) was refluxed at 120 oC for 2 h (till full conversion, LC-MS control) then reaction mixture was cooled to rt. Under an argon atmosphere. N-Fmoc-L-isoleucine (4.1.) (211 mg, 0.60 mmol, 1 eq.), HATU (272 mg, 0.72 mmol, 1.2 eq.) and DIPEA (310 µL, 1.80 mmol, 3 eq.) were added to the solution of free intermediate amine (147 mg, 0.60 mmol). The reaction mixture was stirred for 4 h at room temperature, then diluted with EtOAc (20 mL) washed with H2O (3x10 mL) and then with brine (10 mL). Organic phase was dried over Na2SO4, organic phase was evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane: EtOAc, 2:1 - 1:1– EtOAc to provide 5.1 (253 mg, 73 %) as a solid compound.
[42] 1H NMR (400 MHz, Chloroform-d) d 7.76 (d, J = 7.2 Hz, 2H), 7.68 (t, J = 5.2 Hz, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 6.93 (d, J = 5.7 Hz, 1H), 5.44 (d, J = 8.3 Hz, 1H), 4.45 (dd, J = 10.6, 7.4 Hz, 1H), 4.41– 4.31 (m, 2H), 4.25– 4.18 (m, 2H), 4.14 (dd, J = 8.3, 5.6 Hz, 1H), 4.11– 3.99 (m, 2H), 3.75 (s, 3H), 1.94– 1.79 (m, 1H), 1.60– 1.45 (m, 1H), 1.30 (s, 9H), 1.28– 1.12 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H), 0.98– 0.87 (m, 6H).
13C NMR (101 MHz, Chloroform-d) d 171.1, 170.0, 169.7, 156.3, 144.1, 143.9, 141.4, 127.8, 127.2, 125.3, 125.2, 120.12, 120.10, 75.8, 67.2, 66.1, 59.7, 57.6, 52.4, 47.3, 41.5, 38.1, 28.3, 25.1, 17.2, 15.6, 11.7.
HR-MS (ESI/TOF) calcd for C32H43N3O7Na [M+Na]+ 604.2999, found 604.3001.
[43] By a method analogous to Method B, the following compounds were obtained:
Synthesis of intermediates 6, general method C
[44] Exemplified by the synthesis of 6.1:
[45] A mixture of dipeptide 5.1 (246 mg, 0.42 mmol) in DMF (4 mL) was refluxed at 120 oC for 2 h (till full conversion) then reaction mixture was cooled to rt. Under an argon acetic anhydride (60 µL, 0.63 mmol, 1.5 eq.) and DIPEA (146 µL, 0.84 mmol, 2 eq.) were added to the solution of amine (152 mg, 0.42 mmol, based on a theoretical yield of 100 %). Reaction mixture was stirred for 5 h at room temperature, then diluted with EtOAc (20 mL) washed with H2O (3x10 mL) and then with brine (10 mL). Organic phase was dried over Na2SO4, organic phase was evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane:EtOAc 1:1– EtOAc to provide intermediate 6.1 (114 mg, 67 %) as a solid compound.
[46] 1H NMR (400 MHz, Chloroform-d) d 7.66 (t, J = 5.2 Hz, 1H), 6.91 (d, J = 5.8 Hz, 1H), 6.25 (d, J = 8.3 Hz, 1H), 4.43– 4.33 (m, 2H), 4.16 (qd, J = 6.4, 3.8 Hz, 1H), 4.15– 3.97 (m, 2H), 3.75 (s, 2H), 2.02 (s, 3H), 1.87– 1.76 (m, 1H), 1.57– 1.42 (m, 1H), 1.28 (s, 9H), 1.25– 1.08 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H), 0.96– 0.85 (m, 6H).
13C NMR (101 MHz, Chloroform-d) d 171.2, 170.1, 170.0, 169.6, 75.7, 66.2, 57.8, 57.6, 52.4, 41.5, 38.1, 28.3, 25.3, 23.4, 17.2, 15.5, 11.6.
LC-MS (ESI) calcd for C19H36N3O6 [M+H]+ 402.51, found 402.55.
[47] By a method analogous to Method C, the following compounds were obtained:
[48] Exemplified by the synthesis of 7.1:
[49] Tripeptide 6.1 (114 mg, 0.28 mmol) was dissolved in THF:H2O (20:1, 5 mL), then LiOH (68 mg, 2.84 mmol, 10 eq.) was added and reaction was stirred at room temperature for 20 h. Then water (5 mL) was added and mixture was acidified to pH=~2 by addition of 1 M HCl, then it was extracted with EtOAc (4x5mL). Organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo to provide product 7.1 (107 mg, 97 %) as a white solid. [50] By a method analogous to Method D, the following compounds were obtained:
[52] Exemplified by the synthesis of 9.1:
[53] A mixture of (+)-pinanediol (1R)-(1-aminoethyl)boronate hydrochloride (8.1) (40 mg, 0.15 mmol), 7.1 (60 mg, 0.15 mmol, 1 eq.), HATU (71 mg, 0.19 mmol, 1.2 eq.) and DIPEA
(80 µL, 0.46 mmol, 3 eq.) in DCM (4 mL) was stirred for 2 h at room temperature. The reaction mixture was washed with H2O (2x10 mL) and then with brine (10 mL). Organic phase was dried over Na2SO4, organic phase was evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-5 % MeOH in EtOAc to provide 9.1 (50 mg, 55 %) as a solid compound.
[54] 1H NMR (400 MHz, Chloroform-d) d 7.78 (d, J = 6.4 Hz, 1H), 7.62 (t, J = 5.5 Hz, 1H), 7.54 (d, J = 4.1 Hz, 1H), 6.39 (d, J = 8.5 Hz, 1H), 4.68 (dd, J = 8.5, 6.1 Hz, 1H), 4.40 (dd, J = 6.3, 3.9 Hz, 1H), 4.26 (dd, J = 8.8, 2.1 Hz, 1H), 4.23– 4.00 (m, 3H), 3.07– 2.95 (m, 1H), 2.36– 2.26 (m, 1H), 2.20– 2.09 (m, 1H), 2.06– 1.96 (m, 4H), 1.90– 1.70 (m, 3H), 1.56 – 1.45 (m, 1H), 1.37 (s, 3H), 1.35– 1.23 (m, 13H), 1.20– 1.15 (m, 3H), 1.14– 1.05 (m, 1H), 0.95 (d, J = 6.4 Hz, 3H), 0.91– 0.80 (m, 9H).
13C NMR (101 MHz, Chloroform-d) d 171.4, 170.2, 170.0, 169.4, 85.2, 77.5, 75.6, 66.5, 58.0, 57.5, 51.8, 41.6, 39.8, 38.7, 38.3, 36.0, 33.8, 28.8, 28.9, 27.4, 26.5, 25.0, 24.2, 23.6, 17.6, 16.7, 15.5, 11.7.
HR-MS (ESI/TOF) calcd for C30H54BN4O7 [M+H]+ 593.4086, found 593.4089. Synthesis of boronic acid esters 9, general method F
[55] Exemplified by the synthesis of 9.2:
[56] An acid 7.2 (100 mg, 0.25 mmol, 1 eq.) was dissolved in 5 mL EtOAc, then N- methylmorpholine (85 µL, 3 eq.) and a solution of propylphosphonic acid anhydride (300 µL, 2 eq., 50 % by weight in EtOAc) was added sequentially. Reaction mixture was stirred for 30 min before (+)-pinanediol (1R)-(1-aminoethyl)boronate hydrochloride (8.1) (78 mg, 0.30 mmol, 1.20 eq.) was added. After reaction was complete (LC-MS control) it was diluted with 5 mL of H2O, and HOAc (pH = 3-4) were added. Layers were separated and the aq. layer was extracted with EtOAc (2x5 mL). The combined organic layers were washed with sat. NaHCO3 (10 mL), brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. Crude mixture was purified by flash chromatography on silica gel eluting with 0-5 % MeOH in EtOAc to provide 9.2 (97 mg, 64 %) as a solid compound.
[57] By a method analogous to Method F, the following compounds were obtained:
[59] Exemplified by the synthesis of 10.2:
[60] A solution of 9.2 (73 mg, 0.12 mmol) in MeCN/n-hexane (1:1, 8 mL) was treated with isobutylboronic acid (37 mg, 0.36 mmol, 3 eq.) and 1 M HCl (500 µL). After 18 h at RT, the MeCN phase was washed with n-hexane (3x10 mL) and the n-hexane layer was washed with MeCN (3x10 mL). The combined methanol phase was evaporated in vacuo. Crude product was purified by reversed phase column chromatography to give 10.2 as a white solid (36 mg, 66 %).
[61] By a method analogous to Method G, the following compounds were obtained:
[62] Physicochemical characterization of compounds 10.2-10.8
[63] Exemplified by the synthesis of 11.1:
[64] To a solution of 9.1 (50 mg, 0.08 mmol) in DCM (5 mL), BBr3 (180 µL, 1M solution in DCM) was added dropwise at -78 °C. The mixture was stirred while the temperature was slowly warmed up to ambient temperature. After 2 h, the reaction was quenched with water (10 mL) and the mixture extracted with Et2O (3×10 mL). The aqueous solution was concentrated in vacuo affording 29 mg (85 %) of the product 11.1 as a yellow solid.
[65] 1H NMR (400 MHz, Methanol-d4) d 4.31– 4.07 (m, 5H), 2.82– 2.71 (m, 1H), 2.05 (s, 3H), 1.94– 1.83 (m, 1H), 1.61– 1.50 (m, 1H), 1.28– 1.22 (m, 1H), 1.20 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 7.2 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H).
13C NMR (101 MHz, Methanol-d4) d 176.9, 174.3, 174.2, 173.1, 68.1, 60.5, 60.0, 39.7, 37.6, 26.1, 22.2, 19.91, 15.9, 15.7, 11.4.
HR-MS (ESI/TOF) calcd for C16H30BN4O6 [M-H2O+H]+ 385.2258, found 385.2263 Synthesis of boronic acids 11, general method
[67] A solution of 10.2 (17 mg, 0.038 mmol) in dry DCM (2mL) was treated with TFA (500 µL). Reaction was stirred till completion (LC-MS control). Toluene (5 mL) was added to the reaction mixture and then the solvents were removed. Crude mixture was treated with Et2O (3x5 mL, the precipitate was separated by centrifugation after each addition) to give product 11.2 as a white solid (11 mg, 74 %).
[68] By a method analogous to Method I, the following compounds were obtained:
In vitro Assay [70] The compounds have been tested in vitro as malarial serine protease PfSUB1 inhibitors according to the following process. Determination of IC50
[71] Recombinant purified P. falciparum SUB1 (PfSUB1) was produced and purified as previously described (C. Withers-Martinez, C. Suarez, S. Fulle, S. Kher, M. Penzo, J. P. Ebejer, K. Koussis, F. Hackett, A. Jirgensons, P. Finn, M. J. Blackman, International Journal for Parasitology; 2012, 42, 597). The enzyme was diluted in digestion buffer (25 mM CHAPS, 12 mM CaCl2, 25 mM Tris-HCl, pH 8.2) and dispensed into a white flat-bottomed 96-well fluorescence microtitre plates (Nunc). Test compounds were solubilized in dimethyl sulfoxide (DMSO), serially diluted and added at 2 % to the well. The rhodamine-labelled fluorogenic substrate SERA4st1F-6R12 was added at a final concentration of 0.1 µM in a final volume of 100 µl and the rate of hydrolysis was monitored with a Cary Eclipse spectrofluorimeter (Varian, UK) as previously described. Excitation and emission wavelengths used were 552 nm and 580 nm respectively.
[72] The effects of compounds on growth of blood-stage Plasmodium falciparum (clone 3D7) was assessed using a SYBR Green I assay. Test compounds (dissolved in DMSO at concentrations ranging from 1 mM–0.1 uM) were added in triplicate to wells of flat bottomed, 96 well microtitre plates (1 µL per well). Wells were then supplemented with 100 µL per well of a synchronous P. falciparum parasite culture at 0.1 % parasitaemia, 1 % haematocrit.
[73] Each assay plate also included DMSO only control wells, as well as additional control wells containing uninfected erythrocytes only. Plates were incubated in sealed humidified gassed chambers at 37 oC for 96 h to allow the parasites to undergo two entire cycles of erythrocytic growth. Wells were then supplemented with 100 µL of a 1:5,000 dilution of stock SYBR Green I (Life Technologies, catalogue #S7563) diluted in 20 mM Tris-HCl pH 7.5, 5 mM EDTA, 0.008 % (w/v) saponin, 0.08 % (v/v) Triton X100. Plates were agitated to mix, incubated for a further 1 h in the dark at room temperature, then transferred to a Cary Eclipse fluorescence spectrophotometer (Varian) equipped with a 96-well microplate reader accessory for fluorescence readings (Ex 485 nm, Em 530 nm). EC50 values were determined from dose- response curves obtained after subtracting background fluorescence values (obtained from the erythrocyte only wells) from all experimental readings. Results are given in Table 1.
1. table. Biological activity of boronic acid containing peptidomimetics
Claims
1. A compound with general formula I
wherein:
R4 is H or Me;
R5 is OH;
R8 and R9 taken together represent -CH2-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, R3, R6 , R7 is H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, R12O(CH2)n, R12S(CH2)n,
R12OC(=O)(CH2)n, R12N(R13)C(=O)(CH2)n, R12N (R13)(CH2)n,
Wherein R12 and R13 are independently H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl- C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2- 6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl;
n is an integer selected from 1 to 6;
R1
, R2, R10, R11 are independently
-H, -F, -Cl, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-O-L-OH, -OR14, -O-L-NH2, -O-L-NHR14, -O-L-NR14
2, -O-L-R14NR15, -L-OR14,-O-L-OR14,-OCF3, -O CH2CF3, -OCF2CF2H, -L-OR14,-O-L-OR14,-OCF3, -OCH2CF3, -OCF2CF2H, SR14, SCF3, -CN, -NO2, -NO2, -NH2, -NHR14, -NR14
2, -N(R14)R15,
-L-NH2, -L-NHR14, -L-NR14
2, -L-N(R14) R15,-NH-L-NH2, -NH-L-NHR14,
-NH-L-NR14
2, -NH-L-N(R14)R15,
-NR14-L-NH2, -NR14-L-NHR14, -NR14-L-NR14
2, -NR14-L-N(R14)R15,
L-N(R14)R15,
-C(=O)OH, -C(=O)OR14, -C(=O)NH2, -C(=O)NHR14, -C(=O)NR14
2,
-C(=O)N(R14)R15,-NHC(=O)R14, -NR14C(=O)R15, -NHC(=O)OR14,
-NR14C(=O)OR15, -OC(=O)NH2, -OC(=O)NHR14, -OC(=O)NR14
2,
-OC(=O) R14NR15,-OC(=O)R14, -C(=O)R13,-NHC(=O)NH2, -NHC(=O)NHR14, -NHC(=O)NR14
2, -NHC(=O)N(R14)R15, -NR14C(=O)NH2, -N(R14)C(=O)NHR15,
-NR14C(=O)NR14
2, -NR14C(=O)N
-NHS(=O)2R14, -N(R14)S(=O)2R15,-S(=O)2NH2, -S(=O)2NHR14, -S(=O)2NR14
2, -S(=O)2N(R14)R15,-S(=O)R14, -S(=O)2R14,-OS(=O)2R14,-S(=O)2OR14,
C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, heteroarylthio, 2,3-dihydro-1H-indenyl, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C1-6alkylpiperazino, 4-arylpiperazino,
hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl;
L represents -W-X-Y-Z-; or -W-X-Y, or -W-X; R1 and R2
or R1 and R3
or R7 and R10
or R7 and R11
or R10 and R11 taken together represent -W-X-Y-Z-, or -W-X-Y-, or -W-X- or
wherein
W represents a single bond, oxygen, sulfur, -NR14 or–CR14R15,
X represents oxygen, sulfur, -NR14 or–C(R14)R15,
Y represents oxygen, sulfur, -NR14 or–C(R14)R15,
Z represents oxygen, sulfur, -NR14 or–C(R14)R15;
R14 and R15 are independently H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, heteroarylthio, 2,3-dihydro-1H- indenyl, C1-6alkoxyC1-6alkyl, aryloxyarylC1-6alkoxy, C1-6alkylthio, C4-6alkenylthio, cycloC3-12alkylthio, cycloC3-12alkyl-C1-6alkylthio, cycloC3-12alkyl-C3-6alkenylthio, C1- 6alkoxyC1-6alkylthio, C1-6alkoxyC3-6alkenylthio, arylC3-6alkenylthio, heteroarylC1- 6alkylthio, C1-6alkylsulfonyl, cycloC3-12alkyl-C1-6alkylsulfonyl, arylC1-6alkylsulfonyl, C1-6alkylamino, di-C1-6alkylamino, cycloC3-12alkylamino, C1-C6alkoxy-cycloC3- C12alkylamino, cycloC3-12alkyl-C1-6alkylamino, di-C1-6alkylaminoC1-6alkyl, C1- 6alkoxy-C2-6alkylamino, arylamino, arylC1-6alkylamino, N-cycloC3-12alkyl-N-C1- 6alkylamino, N-aryl-N-C1-6alkylamino, N-arylC1-6alkyl-N-C1-6alkylamino, 2-
indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4- heteroarylpiperidino, morpholino, piperazino, 4-C1-6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, heteroarylC1- 6alkoxy, heteroarylamino, or heteroarylC1-6alkylamino and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof.
2. The compounds according to Claim 1 for use in the treatment of malaria.
3. A pharmaceutical composition, which contains a compound according to Claim 1 and pharmaceutically acceptable carrier for use in the treatment of malaria.
4. The pharmaceutical composition, according to claim 3, wherein said composition is intended for parental or peroral administration.
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---|---|---|---|---|
WO2011109355A1 (en) * | 2010-03-01 | 2011-09-09 | Onyx Therapeutics, Inc. | Compounds for immunoproteasome inhibition |
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---|---|---|---|---|
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WO2014139008A1 (en) * | 2013-03-15 | 2014-09-18 | Adaerata, Limited Partnership | Small molecule modulators of pcsk9 and methods of use thereof |
Non-Patent Citations (11)
Title |
---|
C. WITHERS-MARTINEZC. SUAREZS. FULLES. KHERM. PENZOJ. P. EBEJERK. KOUSSISF. HACKETTA. JIRGENSONSP. FINN, INTERNATIONAL JOURNAL FOR PARASITOLOGY, vol. 42, 2012, pages 597 |
CHOI, S. R.MUKHERJEE, P.AVERY, M. A.: "The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs", CURR. MED. CHEM., vol. 15, 2008, pages 161 - 171 |
CHRISLAINE WITHERS-MARTINEZ ET AL: "subtilisin-like protease 1 (SUB1): Insights into the active-site structure, specificity and function of a pan-malaria drug target", INTERNATIONAL JOURNAL OF PARASITOLOGY, PERGAMON PRESS, GB, vol. 42, no. 6, 12 April 2012 (2012-04-12), pages 597 - 612, XP028513753, ISSN: 0020-7519, [retrieved on 20120427], DOI: 10.1016/J.IJPARA.2012.04.005 * |
FRASINYUK MYKHAYLO S ET AL: "Pentapeptide boronic acid inhibitors ofMycobacterium tuberculosisMycP1protease", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 24, no. 15, 27 May 2014 (2014-05-27), pages 3546 - 3548, XP028864106, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2014.05.056 * |
HYDE, J. E.: "Drug-resistant malaria - an insight", FEBS J., vol. 274, 2007, pages 4688 - 4698 |
KHER SAMIR S ET AL: "Substrate derived peptidic [alpha]-ketoamides as inhibitors of the malarial protease Pf", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 24, no. 18, 7 August 2014 (2014-08-07), pages 4486 - 4489, XP029053324, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2014.07.086 * |
KHER, S. S.PENZO, M.FULLE, S.FINN, P. W.BLACKMAN, M. J.JIRGENSONS, A.: "Substrate derived peptidic a-ketoamides as inhibitors of the malarial protease PfSUBl", BIOORG. MED. CHEM. LETT., vol. 24, no. 18, 2014, pages 4486 - 4489, XP029053324, DOI: 10.1016/j.bmcl.2014.07.086 |
N. K. SAHUS. SAHUD. V. KOHLI: "Novel Molecular Targets for Antimalarial Drug", CHEM. BIOL. DRUG. DES., vol. 71, 2008, pages 287 - 297 |
THOMAS, J. A.TAN, M.S.YBISSON, C.BORG, A.UMREKAR T. RHACKETT FHALE VLVIZCAY-BARRENA GFLECK RASNIJDERS AP: "A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells", NAT MICROBIOL., vol. 3, no. 4, 2018, pages 447 - 455 |
WELLS, T. N.ALONSO, P. L.GUTTERIDGE, W. E.: "New medicines to improve control and contribute to the eradication of malaria", NAT. REV. DRUG DISCOV., vol. 8, 2009, pages 879 - 891 |
WITHERS-MARTINEZ, C.SUAREZ, C.FULLE, S.KHER, S.PENZO, M.EBEJER, J.-P.KOUSSIS, K.HACKETT, F.JIRGENSONS, A.FINN, P.: "Plasmodium subtilisin-like protease 1 (SUB1): Insights into the active-site structure, specificity and function of a pan-malaria drug target", INTERNATIONAL JOURNAL FOR PARASITOLOGY, vol. 42, 2012, pages 597 - 612, XP028513753, DOI: 10.1016/j.ijpara.2012.04.005 |
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