WO2016029324A1 - Modulateurs cd36 à base d'azasulfurylpeptides et utilisations de ceux-ci - Google Patents

Modulateurs cd36 à base d'azasulfurylpeptides et utilisations de ceux-ci Download PDF

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WO2016029324A1
WO2016029324A1 PCT/CA2015/050832 CA2015050832W WO2016029324A1 WO 2016029324 A1 WO2016029324 A1 WO 2016029324A1 CA 2015050832 W CA2015050832 W CA 2015050832W WO 2016029324 A1 WO2016029324 A1 WO 2016029324A1
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peptidomimetic
xaa
mmol
alkyl
ala
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William Lubell
Huy Ong
Stéphane TURCOTTE
Katia MELLAL
Mukandila Mulumba
Lylia DIF YAICHE
Sylvain Chemtob
Samy OMRI
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Rsem, Limited Partnership
Valorisation-Recherche, Limited Partnership
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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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention generally relates to the modulation of CD36, and more specifically to inhibitors of CD36 and their uses.
  • CD36 also known as FAT, SCARB3, GP88, glycoprotein IV (gpIV) and glycoprotein 1Mb (gplllb), is an integral membrane protein found on the surface of many cell types, notably macrophage foam cells, in vertebrate animals.
  • CD36 is a member of the class B scavenger receptor family of cell surface proteins. CD36 has been shown to bind many ligands including collagen, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, oxidized low density lipoproteins, native lipoproteins, oxidized phospholipids, and long-chain fatty acids.
  • TLR2 The Toll-like receptor-2 (TLR2) is co-expressed with CD36, which serves as a co-receptor on TLR2- bearing cells, such as macrophages and microvascular endothelial cells 11 . Furthermore, CD36 has been shown to modulate the inflammatory response mediated by TLR2. Ligands that interact with CD36 may thus have potential to regulate TLR2 signaling pathways by an allosteric mechanism. TLR2 antagonism with an anti-Toll-like receptor-2 antibody was found to reduce the risk of ischemia reperfusion injury 9 , as well as subsequent inflammation following renal transplantation 10 . In the light of the success with an antibody, antagonists of TLR2-mediated signalling are attractive therapeutic targets.
  • Dysregulated or unregulated CD36 activity has been associated with several pathological conditions including atherosclerosis, inflammation (TLR2-related inflammation), abnormal angiogenesis, age-related macular degeneration (dry and/or wet forms), abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion injury, ureteral obstruction, fibrinogenesis in chronic kidney diseases, stroke, Alzheimer's disease, diabetes, diabetic nephropathy and obesity.
  • Z 1 is the native NH 2 terminal group of the peptidomimetic or an amino-terminal modifying group
  • Xaa A is one or two amino acids or amino acid analogs, or is absent;
  • Xaa 1 is L-His, D-His, L-Ala, D-Ala or an analog thereof, or is absent;
  • Xaa 2 is L-Trp, D-Trp or an analog thereof;
  • Xaa 3 is L-Ala, D-Ala or an analog thereof;
  • Xaa 4 is L-Trp, D-Trp or an analog thereof;
  • Xaa 5 is L-Phe, D-Phe or an analog thereof;
  • Xaa 6 is L-Lys, D-Lys or an analog thereof;
  • Z 2 is the native COOH terminal group of the peptidomimetic or a carboxy-terminal modifying group
  • R A and R B are each independently:
  • alkyl, alkenyl, alkynyl and the cycloalkyl and cycloalkenyl are unsubstituted or substituted with one or more R 1 substituents; and wherein the aryl, the heteroaryl, the heterocydyl and the heterobicyclyl are unsubstituted substituted with one or more R 2 substituents,
  • aryl, heteroaryl, heterocydyl, and heterobicyclyl are unsubstituted or substituted with one or more R 2 substituents;
  • aryl, the heteroaryl, the heterocyclyl, and the heterobicyclyl are unsubstituted or substituted with one or more R 7 substituents;
  • R 3 is:
  • alkyl, the alkenyl, the alkynyl and the cycloalkyi are unsubstituted or substituted with one or more R 1 substituents; and wherein the aryl, the heteroaryl, the heterocyclyl and the heterobicyclyl are unsubstituted or substituted with one or more R 2 substituents;
  • R 4 and R 5 are independently chosen from:
  • R 6 is:
  • R 7 is:
  • amino-terminal modifying group is (i) an acyl group (R-CO-), wherein R is a hydrophobic moiety, or (ii) an aroyl group (Ar- CO), wherein Ar is an aryl group.
  • Xaa A is one or two amino acids.
  • Xaa A is Tyr-Ala.
  • peptidomimetic of item 25 wherein said peptidomimetic has the following structure:
  • a method of treating a CD36-related disease, disorder or condition comprising administering to a subject in need thereof an effective amount of the peptidomimetic or pharmaceutically acceptable salt thereof according to any one of items 1 to 27. 29.
  • said disease, disorder or condition is a TLR2-mediated inflammatory disease, disorder or condition.
  • An agent for detecting or monitoring CD36 comprising (a) the peptidomimetic or pharmaceutically acceptable salt thereof according to any one of items 1 to 27, and (b) a detectable moiety attached (e.g., covalently attached) to the peptidomimetic or pharmaceutically acceptable salt thereof.
  • a detectable moiety attached (e.g., covalently attached) to the peptidomimetic or pharmaceutically acceptable salt thereof.
  • said detectable moiety is a radioisotope.
  • Figure 1 shows the packing structure of Cbz-Ala-AsG-D-Phe-Ot-Bu (32b).
  • Figure 2 shows the circular dichroism spectra in water for GHRP-6 (dots), [AzaF 4 ]- GHRP-6 (dashes) and [AsF 4 ]-GHRP-6 (21a, solid line).
  • Figure 3 shows the modulation of TLR2-induced nitrite (NO) production by azasulfurylpeptides 21b-f. ** P ⁇ 0.01 compared to R-FSL-1.
  • Figure 4 shows the kinetic profile of NF- ⁇ signaling pathway modulation by azasulfurylpeptide 21c in peritoneal macrophages, in response to TLR2 ligand (R-FSL-1). * P ⁇
  • Figure 5A shows the profiles of TNFa modulation by CD36 ligands in peritoneal macrophages, in response to TLR2 ligand (R-FSL-1). ** P ⁇ 0.01 compared to R-FSL1 + IFNy (M1).
  • Figure 5B shows the profiles of MCP-1 modulation by CD36 ligands in peritoneal macrophages, in response to TLR2 ligand (R-FSL-1). ** P ⁇ 0.01 compared to R-FSL1 + IFNy (M1).
  • Figure 6A shows the profiles of TNFa modulation by CD36 ligands in CD36-deficient peritoneal macrophages, in response to TLR2 ligand (R-FSL-1). ** P ⁇ 0.01 compared to R- FSL1 + IFNY (M1 ).
  • Figure 6B shows the profiles of MCP-1 modulation by CD36 ligands in CD36-deficient peritoneal macrophages, in response to TLR2 ligand (R-FSL-1). ** P ⁇ 0.01 compared to R- FSL1 + IFNy (M1 ).
  • Figure 7A shows the profiles of TNFa modulation by CD36 ligands in peritoneal macrophages, in response to TLR2/6 ligand LTA. * P ⁇ 0.05 compared to LTA + IFNy (M1).
  • Figure 7B shows the profiles of TNFa modulation by CD36 ligands in peritoneal macrophages, in response to TLR1/2 ligand PAM 3 CSK4.
  • Figure 8A shows the model used to quantitatively assess the activation and recruitment of monocytes/macrophages and microglia in the subretinal space (based on reference 57).
  • Male ApoE " ' " mice (12 weeks) were exposed to blue light using a LED with a transmission peak wavelength of 480 nm and an intensity of 1000 Lux for 5 days, which induces the recruitment of activated macrophages at subretinal levels, which may be monitored using Ionized calcium-Binding Adapter molecule 1 (IBA1 , also known as Allograft Inflammatory Factor
  • IBA1 Ionized calcium-Binding Adapter molecule 1
  • Figure 8B shows the effect of azasulfurylpeptide 21c on subretinal activation/recruitment of activated macrophages/microglia induced by photooxydative stress using the model described above.
  • Male ApoE " ' " mice (12 weeks) were treated with azasulfurylpeptide 21c or the negative control [azal_ys 6 ]-GHRP-6 (43) (daily subcutaneous injection of 300 nmol/kg for 21 days).
  • Figure 9 shows the assessment of retinal degeneration in ApoE "7" mice exposed to blue light.
  • Male ApoE " " mice (12 weeks) were exposed to blue light irradiation at an intensity of 6000 LUX for 5 days, ⁇ . 24 hours after light exposure, mice were treated with azasulfurylpeptide 21c or the negative control [azaLys 6 ]-GHRP-6 (43) for 7 days (daily subcutaneous injection of 300 nmol/kg). Animals were sacrified 3 days after the illumination period, and the eyes were collected. Enucleated eyes were fixed in 4% paraformaldehyde, treated with 30% sucrose, and embedded in oct.
  • Figure 10 shows the kinetics of internalization of Tyr-Ala-21c peptide in J774 macrophage cells.
  • azasulfurylpeptide GHRP-6 analogs bind to CD36 and inhibit TLR2-mediated inflammation in a CD36-dependent manner.
  • the present invention provides a peptidomimetic of formula 1a or 1 b:
  • Z 1 is the native NH 2 terminal group of the peptidomimetic or an amino-terminal modifying group
  • Xaa A is one or two amino acids or amino acid analogs, or is absent;
  • Xaa 1 is L-His, D-His, L-Ala, D-Ala or an analog thereof, or is absent;
  • Xaa 2 is L-Trp, D-Trp or an analog thereof;
  • Xaa 3 is L-Ala, D-Ala or an analog thereof;
  • Xaa 4 is L-Trp, D-Trp or an analog thereof;
  • Xaa 5 is L-Phe, D-Phe or an analog thereof;
  • Xaa 6 is L-Lys, D-Lys or an analog thereof;
  • Z 2 is the native COOH terminal group of the peptidomimetic or a carboxy-terminal modifying group
  • R A and R B are each independently: 1 ) H, 2) Ci-C 6 alkyl, 3) C 2 -C 6 alkenyl, 4) C 2 -C 6 alkynyl, 5) C 3 -C 7 cydoalkyi, 6) C 5 -C 7 cydoalkenyl, 7) haloalkyi, 8) heteroalkyi, 9) aryl, 10) heteroaryl, 11 ) heterobicydyl, or 12) heterocydyl, wherein the alkyl, alkenyl, alkynyl and the cydoalkyi and cydoalkenyl are unsubstituted or substituted with one or more R 1 substituents; and wherein the aryl, the heteroaryl, the heterocydyl and the heterobicydyl are unsubstituted or substituted with one or more R 2 substituents,
  • R 1 is 1) halogen, 2) N0 2 , 3) CN, 4) haloalkyi, 5) C 3 -C 7 cydoalkyi, 6) aryl, 7) heteroaryl, 8) heterocydyl, 9) heterobicydyl, 10) OR 6 , 11 ) S(0) 2 R 3 , 12) NR 4 R 5 , 13) NR 4 S(0) 2 R 3 , 14) COR 6 , 15) C(0)OR 6 , 16) CONR 4 R 5 , 17) S(0) 2 NR 4 R 5 , 18) OC(0)R 6 , 19) SC(0)R 3 , 20) NR 6 C(0)NR 4 R 5 , 21 ) heteroalkyi, 22) NR 6 C(NR 6 )NR 4 R 5 , or 23) C(NR 6 )NR 4 R 5 ; wherein the aryl, heteroaryl, heterocydyl, and heterobicydyl are unsubstituted or substituted with
  • R 2 is 1) halogen, 2) N0 2 , 3) CN, 4) C-i-C 6 alkyl, 5) C 2 -C 6 alkenyl, 6) C 2 -C 4 alkynyl, 7) C 3 - C 7 cydoalkyi, 8) haloalkyi, 9) OR 6 , 10) NR 4 R 5 , 11) SR 6 , 12) COR 6 , 13) C(0)OR 6 , 14) S(0) 2 R 3 , 15) CONR 4 R 5 , 16) S(0) 2 NR 4 R 5 , 17) aryl, 18) heteroaryl, 19) heterocydyl, 20) heterobicydyl, 21 ) heteroalkyi, 22) NR 6 C(NR 6 )NR 4 R 5 , or 23) C(NR 6 )NR 4 R 5 , wherein the aryl, the heteroaryl, the heterocydyl, and the heterobicydyl are unsubstit
  • R 4 and R 5 are independently chosen from: 1 ) H, 2) C C 6 alkyl, 3) C 2 -C 6 alkenyl, 4) C 2 -C 6 alkynyl, 5) aryl, 6) heteroaryl, or 7) heterocyclyl, or R 4 and R 5 together with the nitrogen to which they are bonded form a heterocyclic ring;
  • R 6 is: 1) H, 2) Ci-C 6 alkyl, 3) C 2 -C 6 alkenyl, 4) C 2 -C 6 alkynyl, 5) aryl, 6) heteroaryl, or 7) heterocyclyl;
  • R 7 is: 1) halogen, 2) N0 2 , 3) CN, 4) C C 6 alkyl, 5) C 2 -C 6 alkenyl, 6) C 2 -C 4 alkynyl, 7) C 3 - C 7 cycloalkyl, 8) haloalkyl, 9) OR 6 , 10) NR 4 R 5 , 11) SR 6 , 12) COR 6 , 13) C(0)OR 6 , 14) S(0) 2 R 3 , 15) CONR 4 R 5 , 16) S(0) 2 NR 4 R 5 , 17) heteroalkyl, 18) NR 6 C(NR 6 )NR 4 R 5 , or 19) C(NR 6 )NR 4 R 5 ; or a pharmaceutically acceptable salt thereof.
  • peptidomimetic refers to a compound comprising a plurality of amino acid residues (naturally- and/or non-naturally-occurring amino acids, amino acid analogs) joined by a plurality of peptide and/or non-peptide bonds and at least one azasulfuryl residue.
  • the peptidomimetic optionally include one or more non-peptide bonds between one or more amino acid residues and/or amino acid analog residues, and optionally include one or more non-naturally-occurring amino acid residues or amino acid analog residues in addition to the at least one azasulfuryl residue.
  • analog when used in reference to an amino acid refers to synthetic amino acids providing similar side chain functionality (i.e., structurally similar) as the "native" amino acid and which can be substituted for an amino acid in the formation of a peptidomimetic.
  • Amino acid analogs include, without limitation, ⁇ -amino acids and amino acids, in which the amino or carboxy group is substituted by a similarly reactive group or other groups (e.g., substitution of the primary amine with a secondary or tertiary amine, or substitution of the carboxy group with an ester).
  • aromatic amino acids may be replaced with D- or L-naphthylalanine, D- or L-homophenylalanine, D- or L-phenylglycine, D- or L-2-thienylalanine, D- or L-1-, 2-, 3-, or 4- pyrenylalanine, D- or L-3-thienylalanine, D- or L-(2-pyridinyl)-alanine, D- or L-(3-pyridinyl)-alanine, D- or L-(2-pyrazinyl)-alanine, D- or L-(4-isopropyl)-phenylglycine, D-(trifluoromethyl)- phenylglycine, D-(trifluoromethyl)-phenylalanine, D-p-fluorophenylalanine, D- or L-p- biphenylalanine D-or L-p-methoxybiphenylalanine, D- or
  • substitutions may include unnatural alkylated amino acids, made by combining an alkyl group with a natural amino acid.
  • Basic natural amino acids such as lysine and arginine may be substituted with alkyl groups at the amine (NH 2 ) functionality.
  • substitutions include nitrile derivatives (e.g., containing a CN-moiety in place of the CONH 2 functionality) of asparagine or glutamine, and sulfoxide derivative of methionine.
  • Cysteinyl residues may be reacted with alpha-haloacetates (and corresponding amines), such as 2-chloroacetic acid or chloroacetamide, to give carboxymethyl or carboxyamidomethyl derivatives.
  • Histidyl residues may be derivatized by reaction with compounds such as diethylprocarbonate e.g., at pH 5.5-7.0 because this agent is relatively specific for the histidyl side chain, and para-bromophenacyl bromide may also be used; e.g., where the reaction is preferably performed in 0.1 M sodium cacodylate at pH 6.0.
  • Lysinyl and amino terminal residues may be reacted with compounds such as succinic or other carboxylic acid anhydrides.
  • Suitable reagents for derivatizing alpha-amino-containing residues include compounds such as imidoesters, e.g., methyl picolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride; trinitrobenzenesulfonic acid; O-methylisourea; 2,4 pentanedione; and transaminase-catalyzed reaction with glyoxylate.
  • Arginyl residues may be modified by reaction with one or several conventional reagents, among them phenylglyoxal, 2,3-butanedione, 1 ,2-cyclohexanedione, and ninhydrin according to known method steps. Derivatization of arginine residues is typically performed in alkaline conditions because of the high pKa of the guanidine functional group. Furthermore, these reagents may react with the groups of lysine as well as the arginine epsilon-amino group.
  • tyrosinyl residues per se are well-known, such as for introducing spectral labels into tyrosinyl residues by reaction with aromatic diazonium compounds or tetranitromethane.
  • N-acetylimidazol and tetranitromethane may be used to form O-acetyl tyrosinyl species and 3-nitro derivatives, respectively.
  • Tryptophan residues may be methylated at position 2 (sometimes referred to as 2Me-Trp or Mrp).
  • aspartyl and glutamyl residues may be converted to asparaginyl and glutaminyl residues by reaction with ammonium ions.
  • Glutaminyl and asparaginyl residues may be frequently deamidated to the corresponding glutamyl and aspartyl residues.
  • modifications of the above-mentioned peptide analog/azasulfurylpeptide may include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the alpha-amino groups of lysine, arginine, and histidine side chains acetylation of the N-terminal amine, methylation of main chain amide residues (or substitution with N-methyl amino acids) and, in some instances, amidation of the C-terminal carboxyl groups, according to known method steps.
  • Analogs of histidine include those described in Ikeda ef a/., Protein Eng. (2003) 16 (9): 699-706 (e.g., 3-(1 ,2,3-triazol-4-yl)-DL-alanine), those described in Stefanucci et al., Int. J. Mol. Sci.
  • Analogs of tryptophan includes 2Me-Trp (or Mrp), 5-Methyl-DL-tryptophan, azatryptophan (7-azatryptophan), hydroxytryptophan (5-hydroxytryptophan), fluorotryptophan, aminotryptophan, tryptamine and desaminotryptophan, a-methyl-tryptophan; -(3-benzothienyl)- D-alanine; 3-(3-benzothienyl)-L-alanine; 1-methyl-tryptophan; 4-methyl-tryptophan; 5-benzyloxy- tryptophan; 5-bromo-tryptophan; 5-chloro-tryptophan; 5-fluoro-tryptophan; 5-hydroxytryptophan; 5-hydroxy-L-tryptophan; 5-methoxy-tryptophan; 5-methoxy-L-tryptophan; 5-methyl- tryptophan; 6-bromo-tryptophan; 6-chloro
  • Analogs of alanine include ⁇ -alanine, aminoisobutyric acid (a or ⁇ ), methylalanine and f-butylalanine.
  • Analogs of phenylalanine include ⁇ -methyl-phenylalanine, ⁇ -hydroxyphenylalanine, a- methyl-3-methoxy-DL-phenylalanine, a-methyl-D-phenylalanine, a-methyl-L-phenylalanine, 2,4- dichloro-phenylalanine, 2-(trifluoromethyl)-D-phenylalanine, 2-(trifluoromethyl)-L-phenylalanine, 2-bromo-D- phenylalanine, 2-bromo-L-phenylalanine, 2-chloro-D-phenylalanine, 2-chloro-L- phenylalanine, 2-cyano-D-phenylalanine, 2-cyano-L-phenylalanine, 2-fluoro-D-phenylalanine, 2- fluoro-L-phenylalanine, 2-methyl-D-phenylalanine, 2-methyl-L-phenylalanine, 2-nitro-D
  • Analogs of lysine include the related amino acid arginine and analogs thereof such as citrulline; L-2-amino-3-guanidinopropionic acid; L-2-amino-3-ureidopropionic acid; L-citrulline; Lys(Me) 2 -OH; Lys(N 3 )-OH; ⁇ -benzyloxycarbonyl-L-ornithine; ⁇ -nitro-D-arginine; ⁇ -nitro-L- arginine; a-methyl-ornithine; 2,6-diaminoheptanedioic acid; L-ornithine; (N5-1-(4,4-dimethyl-2,6- dioxo-cyclohex-1 -ylidene)ethyl)-D-ornithine; ( ⁇ -1 -(4,4-dimethyl-2,6-dioxo-cyclohex-1 - ylidene)ethyl
  • halogen refers to fluorine, chlorine, bromine or iodine or a radical thereof.
  • the benzyl is substituted with at least one fluoride (F), in a further embodiment the fluoride is in position 4 of the benzene ring.
  • R is a benzyl substituted with an O-R 2 group, wherein R 2 is alkyl, alkenyl or alkynyl.
  • alkyl refers to a hydrocarbon chain that is a straight chain or branched chain, containing the indicated number of carbon atoms.
  • C1-C10 indicates that the group has from 1 to 10 (inclusive) carbon atoms in it.
  • alkyl is a chain (straight or branched) having 1 to 20 (inclusive) carbon atoms in it.
  • the alkyl is a C1-C12 alkyl, in a further embodiment a Ci-C 6 alkyl or a C1-C3 alkyl.
  • heteroalkyl refers to an alkyl as described above in which at least one carbon of the alkyl is replaced by a heteroatom, for example N, O, P, B, S, Si, Sb, Al, Sn, As, Se or Ge.
  • alkenyl refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon double bonds.
  • the alkenyl moiety contains the indicated number of carbon atoms.
  • C 2 -C 10 indicates that the group has from 2 to 10 (inclusive) carbon atoms in it.
  • alkenyl is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it.
  • the alkenyl" is a C2-C12 alkenyl, in a further embodiment a C2-C6 alkenyl or a C2-C3 alkenyl.
  • alkynyl refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon triple bonds.
  • the alkynyl moiety contains the indicated number of carbon atoms.
  • C 2 -Ci 0 indicates that the group has from 2 to 10 (inclusive) carbon atoms in it.
  • alkynyl is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it.
  • the alkynyl is a C 2 -C 12 alkynyl, in a further embodiment a C 2 -C 6 alkynyl or a C 2 -C 3 alkynyl.
  • aryl means mono- or bicyclic carbocyclic ring system having 6 to ten carbon atoms forming one or two aromatic rings and is exemplified by phenyl, naphthyl, 1 ,2-dihydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, tolyl, alkyloxyphenyl, alkyloxycarbonylphenyl, halophenyl and the like, and may be optionally substituted with one, two, three, four, five or six substituents located at any position of the ring.
  • the aryl is benzyl.
  • the benzyl is substituted with at least one halogen.
  • substituted benzyl refers to a group replacing a second atom or group such as a hydrogen atom on any molecule, compound or moiety.
  • the substituted benzyl may comprise 1 , 2, 3, 4 or 5 substituent(s).
  • the substituted benzyl comprises 1 substituent. At least one substituent may be present in positions 2, 3, 4, 5 and/or 6 of the benzene ring. In an embodiment, at least one substituent is in position 4 of the benzene ring.
  • Carbocyclo or “carbocyclic”, used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring systems, as described herein, having from 3 to 10 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein.
  • Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl.
  • the cycloalkyl has 3-6 carbons.
  • cycloaliphatic also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl, tetrahydronaphthyl, decalin, or bicyclo[2.2.2]octane, where the radical or point of attachment is on an aliphatic ring.
  • heteroarylalkyl means an alkyi group (e.g., a lower alkyi group) where one of the hydrogens is substituted with heteroaryl. Heteroarylalkyl groups may be unsubstituted or substituted with, for example, 1 , 2, 3, 4, 5, 6, or 7 substituent groups.
  • arylalkyl means an alkyi group (e.g., a lower alkyi group) where one of the hydrogens is substituted with aryl (e.g., benzene, naphthalene, anthracene, or phenanthrene).
  • aryl e.g., benzene, naphthalene, anthracene, or phenanthrene
  • exemplary arylalkyl groups include benzyl and phenethyl.
  • Arylalkyl groups may be unsubstituted or substituted with, for example, 1 , 2, 3, 4, 5, 6, or 7 substituent groups located at any position (i.e., on the sp 2 or the sp 3 hybridized carbons of the group).
  • heteroaryl represents that subset of heterocycles, as defined herein, which are aromatic: i.e., they contain 4n+2 pi electrons within the mono- or multicyclic ring system.
  • Illustrative examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzotriazinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl
  • Five- or six-membered monocyclic heteroaryl rings include: pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like.
  • Eight- to ten-membered bicyclic heteroaryl rings having one to four heteroatoms include: quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzotriazinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, indazolyl, and the like.
  • Heteroaryls may be unsubstituted or substituted with 1 , 2, 3, 4, 5, or 6 substituents.
  • optional substituents include, but are not limited to: hydroxy (-OH), -CN, -N0 2 , halogen (i.e., -F, -CI, -Br, or -I), -C0 2 H, -C0 2 (lower alkyi), - C0 2 (lower alkoxyalkyl), -(lower alkyi), -(lower alkoxyalkyl), -0(lower alkyi), -0(lower alkoxyalkyl), -NH(lower alkyi), -NH(lower alkoxyalkyl), -N(lower alkyl) 2 , and -N(lower alkoxyalkyl) 2 .
  • a substituted group may have 1 , 2, 3, 4, 5, 6, 7, 8, or 9 substituents located at any position.
  • a substituent group that includes lower alkyi or lower alkoxy is further substituted
  • R A is alkyi, alkenyl or alkynyl, or a substituted benzyl, wherein at least one of said substituent is a halogen (e.g., F) or an O-R 8 group, wherein R 8 is alkyi, alkenyl or alkynyl, preferably a C C 3 alkyi such as a methyl.
  • the substituted benzyl is a 4-substituted benzyl.
  • R A is alkyi, alkenyl or alkynyl, or a substituted benzyl, wherein at least one of said substituent is a halogen (e.g., F) or an O-R 8 group, wherein R 8 is alkyi, alkenyl or alkynyl, preferably a C C 3 alkyi such as a methyl.
  • the substituted benzyl is a 4-substituted benzyl.
  • R A is alkyi, alkenyl or
  • R is H, alkyl, alkenyl or alkynyl, preferably a C 1 -C3 alkyl such as a methyl.
  • Xaa 1 is L-His
  • Xaa 2 is D-Trp
  • Xaa 3 is L-Ala
  • Xaa 4 is L-Trp
  • Xaa 5 is D- Phe and/or Xaa 6 is L-Lys.
  • Z is NH 2 (the peptide has a native NH 2 terminal group, i.e. the NH 2 group of Xaa A , Xaa 1 (when Xaa A is absent) or Xaa 2 (when Xaa A and Xaa 1 are absent).
  • Z 1 is an amino-terminal modifying group.
  • amino-terminal modifying group refers to a moiety commonly used in the art of peptide chemistry to replace or modify the native NH 2 terminal group of the peptide, for example to increase its stability and/or susceptibility to protease digestion.
  • Z is N-R 9 R 10 or NH-R 9 wherein R 9 and/or R 0 is a straight chained or branched alkyl group of one to eight carbons, or an acyl group (R -CO-), wherein R 1 is a hydrophobic moiety (e.g., acetyl, propionyl, butanyl, iso-propionyl, or iso-butanyl), or an aroyl group (Ar-CO-), wherein Ar is an aryl group.
  • R 9 and/or R 0 is a straight chained or branched alkyl group of one to eight carbons, or an acyl group (R -CO-), wherein R 1 is a hydrophobic moiety (e.g., acetyl, propionyl, butanyl, iso-propionyl, or iso-butanyl), or an aroyl group (Ar-CO-), wherein Ar is an aryl group.
  • the acyl group is a Ci-Ci 6 or C 3 -Ci 6 acyl group (linear or branched, saturated or unsaturated), in a further embodiment, a saturated C Ce acyl group (linear or branched) or an unsaturated C 3 -C 6 acyl group (linear or branched), for example an acetyl group (CH 3 -CO-, Ac).
  • Z 2 is COOH (the peptidomimetic has a native COOH terminal, i.e. the COOH group of Xaa 6 ).
  • Z 2 is a carboxy-terminal modifying group (e.g., attached via an ester linkage).
  • carboxy-terminal modifying group refers to a moiety commonly used in the art of peptide chemistry to replace or modify the native COOH terminal group of the peptide/peptidomimetic, for example to increase its stability and/or susceptibility to protease digestion.
  • Z 2 is an hydroxamate group, an amide (primary, secondary or tertiary) group, COR 12 wherein R 12 is a nitrile group, an aliphatic amine of one to ten carbons such as methyl amine, iso-butylamine, iso-valerylamine or cyclohexylamine, an aromatic or arylalkyl amine such as aniline, napthylamine, benzylamine, cinnamylamine, or phenylethylamine, an alcohol or CH 2 OH.
  • Z 2 is an amide, more particularly CONH 2 .
  • Xaa A is absent. In another embodiment, Xaa A is two amino acids. In further embodiment, Xaa A is Tyr-Ala.
  • the peptidomimetic has the following structure: In an embodiment, the peptidomimetic has the following structure: In an
  • the present invention provides azasulfuryl-containing peptidomimetics of other CD36 modulatory peptides (i.e. in which one or more amino acids are replaced with an azasulfuryl moiety).
  • CD36 modulatory peptides comprising aza inter-amino acid linkage are described, for example, in PCT publication No. WO2008/157738 and U.S. Patent Pub. No. 20100279941.
  • peptides having the following sequences: (D/L)His-AzaPhe-Ala-Ala-D-Phe-Lys; Ala-AzaPhe-Ala-Trp-D-Lys; His- AzaTyr-Ala-Trp-D-Phe-Ala; Ala-AzaTyr-Ala-Trp-D-Phe-Lys; His-D-Trp-AzaLeu-Trp-Ala-Lys; His- D-Trp-AzaLeu-Ala-D-Phe-Lys; Phe-D-Trp-Ala-AzaTyr-D-Phe-Lys; Ala-D-Trp-Ala-AzaTyr-D-Phe- Lys; Hydrocinnamyl-D-Trp-Ala-AzaTyr-D-Phe-Lys; Ala-D-Trp-Ala-Aza
  • the peptidomimetics of this invention contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are included in the present invention unless expressly provided otherwise.
  • the peptidomimetics of this invention are also represented in multiple tautomeric forms, in such instances, the invention includes all tautomeric forms of the compounds described herein. All such isomeric forms of such compounds are included in the present invention unless expressly provided otherwise. All crystal forms of the compounds described herein are included in the present invention unless expressly provided otherwise.
  • the above-mentioned peptidomimetics are in the form of a salt, e.g., a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt refers to salts of compounds that retain the biological activity of the parent compound, and which are not biologically or otherwise undesirable. Such salts can be prepared in situ during the final isolation and purification of the analog, or may be prepared separately by reacting a free base function with a suitable acid.
  • Many of the peptidomimetics disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Acid addition salts may be prepared from inorganic and organic acids.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, decanoate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, octanoate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyan
  • Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include, for example, an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, and phosphoric acid, and an organic acid, e.g., oxalic acid, maleic acid, succinic acid, and citric acid.
  • an inorganic acid e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, and phosphoric acid
  • organic acid e.g., oxalic acid, maleic acid, succinic acid, and citric acid.
  • Basic addition salts also can be prepared by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like, and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium, amongst others.
  • Other representative organic amines useful for the formation of base addition salts include, for example, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines.
  • the above-mentioned peptidomimetic is substantially pure.
  • a compound is "substantially pure” when it is separated from the components that naturally accompany it.
  • a compound is substantially pure when it is at least 60%, more generally 75%, 80% or 85%, preferably over 90% and more preferably over 95% (96, 97, 98 or 99%), by weight, of the total material in a sample. Purity can be measured using any appropriate method such as column chromatography, gel electrophoresis, HPLC, etc.
  • the peptidomimetics may be modified to facilite their detection, for example by covalent attachment of a detectable moiety or tag, such as bioluminescent, fluorescent and/or radioactive moieties.
  • a detectable moiety or tag such as bioluminescent, fluorescent and/or radioactive moieties.
  • the present invention provides an agent for detecting or monitoring CD36, said agent comprising (a) the peptidomimetic or pharmaceutically acceptable salt thereof as defined herein, and (b) a detectable moiety covalently attached to the peptidomimetic or pharmaceutically acceptable salt thereof.
  • the term "detectable moiety” refers to a moiety emitting a signal (e.g., light, radioactivity) that may be detected using an appropriate detection system.
  • Detectable moieties include, for example, enzyme or enzyme substrates, reactive groups, chromophores such as dyes or colored particles, luminescent moieties including a bioluminescent, phosphorescent or chemiluminescent moieties, fluorescent moieties, and radioisotopes (radionuclides).
  • the detectable moiety is a radioisotope, for example 125 l.
  • the detectable moiety can be joined, directly or indirectly, to the peptidomimetic.
  • Direct labeling can occur through bonds or interactions that link the label to the peptidomimetic (e.g., covalent bonds or non- covalent interactions), whereas indirect labeling can occur through the use of a "linker” or bridging moiety, which is either directly or indirectly labeled.
  • the above-defined agent may be used to detect or monitor CD36 at the surface and/or in a cell.
  • the peptidomimetics of the present invention may also comprise modifications that confer additional biological properties to the peptidomimetics such as protease resistance, plasma protein binding, increased plasma half-life, intracellular penetration, etc.
  • modifications include, for example, covalent attachment of fatty acids (e.g., C 6 -Ci 8 ) to the peptidomimetics, attachment to proteins such as albumin (see, e.g., U.S. Patent No. 7,268,113); glycosylation, biotinylation or PEGylation (see, e.g., U.S. Patent Nos. 7,256,258 and 6,528,485).
  • fatty acids e.g., C 6 -Ci 8
  • proteins such as albumin
  • glycosylation, biotinylation or PEGylation see, e.g., U.S. Patent Nos. 7,256,258 and 6,528,485.
  • Peptides (including the peptide portions of peptidomimetics) of the present invention are obtained by any method of peptide synthesis known to those skilled in the art, including synthetic (e.g., exclusive solid phase synthesis, partial solid phase synthesis, fragment condensation, classical solution phase synthesis).
  • the peptides or peptide derivatives can be obtained by solid-phase peptide synthesis, which in brief, consists of coupling the carboxyl group of the C-terminal amino acid to a resin (e.g., benzhydrylamine resin, chloromethylated resin, hydroxymethyl resin) and successively adding N-alpha protected amino acids.
  • the protecting groups maybe any such groups known in the art.
  • the peptidomimetics are produced according to the methods employing N- aminosulfamide building blocks described at Example 1 below.
  • any process of the preparation of a peptidomimetics of the present invention it may be desirable to protect sensitive reactive groups on any of the molecule concerned. This may be achieved by means of conventional protecting groups such as those described in Protective Groups In Organic Synthesis by T.W. Greene & P. G. M. Wuts, 1991 , John Wiley and Sons, New York; and Peptides: chemistry and Biology by Sewald and Jakubke, 2002, Wiley- VCH, Wheinheim p.142.
  • alpha amino protecting groups include acyl type protecting groups (e.g., trifluoroacetyl, formyl, acetyl), aliphatic urethane protecting groups (e.g., f-butyloxycarbonyl (BOC), cyclohexyloxycarbonyl), aromatic urethane type protecting groups (e.g., fluorenyl-9-methoxy-carbonyl (Fmoc), Fmoc derivatives, benzyloxycarbonyl (Cbz), Cbz derivatives) and alkyl type protecting groups (e.g., triphenyl methyl, benzyl).
  • acyl type protecting groups e.g., trifluoroacetyl, formyl, acetyl
  • aliphatic urethane protecting groups e.g., f-butyloxycarbonyl (BOC), cyclohexyloxycarbonyl
  • aromatic urethane type protecting groups e.g.
  • the amino acids side chain protecting groups include benzyl (For Thr and Ser), Cbz (Tyr, Thr, Ser, Arg, Lys), methyl ethyl, cyclohexyl (Asp, His), Boc (Arg, His, Cys) etc.
  • the protecting groups may be removed at a convenient subsequent stage using methods known in the art.
  • the peptidomimetics of the invention can be purified by many techniques of peptide purification well known in the art, such as reverse phase chromatography, high performance liquid chromatography (HPLC), ion exchange chromatography, size exclusion chromatography, affinity chromatography, gel electrophoresis, and the like.
  • HPLC high performance liquid chromatography
  • ion exchange chromatography size exclusion chromatography
  • affinity chromatography gel electrophoresis, and the like.
  • affinity chromatography purification any antibody, which specifically binds the peptide or peptide analog may for example be used.
  • the processes for the preparation of the peptidomimetics according to the present invention give rise to mixtures of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their components enantiomers by standard techniques such as the formation of diastereoisomeric pairs by salt formation with an optically active acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral HPLC column.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned peptidomimetics and one or more pharmaceutically acceptable carriers, diluents and/or excipients.
  • Such compositions may be prepared in a manner well known in pharmaceutical art.
  • Supplementary active compounds can also be incorporated into the compositions.
  • pharmaceutically acceptable carrier includes any and all solvents, buffers, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier can be suitable, for example, for oral, intravenous, parenteral, topical, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, subconjunctival, ophthalmic, intraventricular, intracapsular, intraspinal, intrathecal, epidural, intracisternal, intraperitoneal, intranasal, intrauterine, intramyometrial, sublingual, vaginal, rectal, epidural or pulmonary (e.g., aerosol) administration (see Remington: The Science and Practice of Pharmacy by Alfonso R. Gennaro, 2003, 21 st edition, Mack Publishing Company).
  • pharmaceutically acceptable refers to materials characterized by the absence of (or limited) toxic or adverse biological effects in vivo. It refers to those compounds, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the biological fluids and/or tissues and/or organs of a subject (e.g., human, animal) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compositions within the scope of the present invention should contain the active agent
  • a peptidomimetic in an amount effective to achieve the desired therapeutic effect while minimizing adverse side effects.
  • Pharmaceutically acceptable preparations and salts of the active agent are within the scope of the present invention and are well known in the art.
  • the amount administered should be chosen so as to minimize adverse side effects.
  • the amount of the therapeutic or pharmaceutical composition which is effective in the treatment of a particular disease, disorder or condition will depend on the nature and severity of the disease, the target site of action, the patient's weight, special diets being followed by the patient, concurrent medications being used, the administration route and other factors that will be recognized by those skilled in the art.
  • the dosage will be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters from the patient. Typically, 0.001 to 100 mg/kg/day will be administered to the subject. Effective doses may be extrapolated from dose response curves derived from in vitro or animal model test systems. For example, in order to obtain an effective mg/kg dose for humans based on data generated from rat studies, the effective mg/kg dosage in rat is divided by six.
  • the peptidomimetics have the ability to modulate (e.g., inhibit) CD36 activity (CD36 modulators).
  • CD36 modulators refers to a compound that alters or elicits an activity of CD36.
  • the presence of a modulator may result in an increase or decrease in the magnitude of a certain activity compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor or antagonist, which decreases the magnitude of one or more activities.
  • an inhibitor completely prevents one or more biological activities.
  • the terms “inhibiting,” “reducing,” “preventing,” or “antagonizing,” or any variations of these terms as used herein, refer to a measurable decrease of a biological activity. In some embodiments, the decrease is a 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% reduction in the biological activity relative to a control.
  • CD36 also known as FAT, SCARB3, GP88, glycoprotein IV (gpIV) and glycoprotein 1Mb (gplllb), is an integral membrane protein found on the surface of many cell types in vertebrate animals.
  • CD36 is a member of the class B scavenger receptor family of cell surface proteins. CD36 has been shown to bind many ligands including collagen, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, oxidized low density lipoproteins, native lipoproteins, oxidized phospholipids, and long-chain fatty acids.
  • CD36 was also shown to be involved in Toll-Like Receptor 2 (TLR2) signaling (i.e., to act as a co-receptor for TLR2), and more specifically signaling through TLR2 TLR6 heterodimers.
  • TLR2 is able to recognize a diverse set of pathogen-associated motifs including several components of Gram-positive bacteria such as peptidoglycan, lipoteichoic acid (LTA), lipoarabinomanan, lipoproteins, as well as different LPS from certain Gram-negative bacteria, yeast, spirochete, and fungi. Its promiscuity has been attributed to its unique ability to heterodimerize with TLRs 1 and 6.
  • TLR2 heteromer usage has mainly been investigated using bacterial lipoproteins.
  • Studies using diacylated and triacylated lipoproteins have revealed that diacylated lipoproteins require TLR2/6 heterodimers for activation, whereas triacylated lipoproteins induce activation of the innate immune system independently of TLR6 and mainly through TLR2/TLR1 heterodimers.
  • TLR2/TLR6 heterodimers have shed more light into TLR2 heterotypic associations by demonstrating that TLR2/TLR6 heterodimers also require CD36 to sense diacylated lipoproteins, whereas TLR2 TLR1 heterodimers do not.
  • the present invention provides a method for modulating CD36 activity in a cell, said method comprising contacting the cell with an effective amount of the peptidomimetic or pharmaceutically acceptable salt thereof defined herein.
  • the present invention also provides the use of the peptidomimetic or pharmaceutically acceptable salt thereof defined herein for modulating CD36 activity in a cell.
  • the present invention also provides the use of the peptidomimetic or pharmaceutically acceptable salt thereof defined herein for the manufacture of a medicament for modulating CD36 activity in a cell.
  • the present invention also provides the peptidomimetic or pharmaceutically acceptable salt thereof defined herein for modulating CD36 activity in a cell. In an embodiment, the modulating is inhibiting.
  • the peptidomimetics of the present invention are useful in the treatment of CD36-related diseases, disorders or conditions.
  • the present invention relates to a method for inhibiting or antagonizing CD36 activity through its interaction with the peptidomimetics of the present invention.
  • diseases and conditions associated with CD36 activity include, but are not limited to atherosclerosis, inflammation (TLR2-related inflammation), abnormal angiogenesis, age-related macular degeneration (dry and/or wet forms), abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion injury, ureteral obstruction, fibrinogenesis in chronic kidney diseases, stroke, Alzheimer's Disease, diabetes, diabetic nephropathy and obesity.
  • the present invention provides a method for reducing or inhibiting
  • TLR2-related inflammation e.g., TLR2/6-related inflammation
  • a biological system cells, subject
  • the present invention provides a method for reducing or inhibiting the production of nitric oxide (NO) induced by TLR2 activation/stimulation in a cell, said method comprising contacting said cell with a peptidomimetic as defined herein.
  • the present invention also relates to the treatment of medical conditions involving the activation of TLR2 (e.g., TLR2/6), and especially immune-mediated and inflammatory diseases.
  • TLR2 has also been implicated to have a role in a wide variety of allergic- and immune-mediated inflammatory diseases such as sepsis, ischemia/reperfusion injury to heart or kidneys, cardiovascular disease and atherosclerosis, allergies, asthma, atopy, atopic dermatitis, arthritis (rheumatoid arthritis), systemic lupus erymathosis (SLE), and diabetes (O'Neill et al., 2009, Pharmacol. Rev., vol. 61 , p. 177).
  • allergic- and immune-mediated inflammatory diseases such as sepsis, ischemia/reperfusion injury to heart or kidneys, cardiovascular disease and atherosclerosis, allergies, asthma, atopy, atopic dermatitis, arthritis (rheumatoid arthritis), systemic lupus erymathosis (SLE), and diabetes (O'Neill et al., 2009, Pharmacol. Rev., vol. 61 , p. 177).
  • the CD36-related disease, disorder or condition is atherosclerosis, age-related macular degeneration (dry and/or wet forms), fibrinogenesis in chronic kidney diseases or myocardial ischemia/reperfusion injury.
  • the present invention provides the use of the peptidomimetics as defined herein for the treatment of a CD36-related disease, disorder or condition as defined above. In another aspect, the present invention provides the use of the peptidomimetics as defined herein for the manufacture of a medicament for the treatment of a CD36-related disease, disorder or condition as defined above. In another aspect, the present invention provides the peptidomimetics as defined herein for the treatment of a CD36-related disease, disorder or condition as defined above.
  • an azasulfuryl residue has been introduced at position 3 or 4 of GHRP-6 to prepare the peptidomimetics.
  • active azasulfuryl-containing peptidomimetics or N-Aminosulfamides peptidomimetics
  • the present invention provides a method of obtaining an azasulfuryl- containing peptidomimetic capable of modulating (e.g., inhibiting) CD36 activity, said method comprising:
  • GHRP-6 peptide refers to native GHRP-6 (sequence: His-D-Trp- Ala-Trp-D-Phe-Lys-NH 2 ) as well as to GHRP-6 analogs such as hexarelin (sequence: His-D- 2MeTrp-Ala-Trp-D-Phe-Lys-NH 2 , azapeptide analogs disclosed in PCT publication No. WO2008/157738 and U.S. Patent Pub. No.
  • any of these GHRP-6 peptides may be used as the starting compound to prepare azasulfuryl-containing peptidomimetics, by replacing one or more of the residues with an azasulfuryl residue to obtain an azasulfuryl-containing peptidomimetic.
  • Azasulfuryl residue refers to an amino acid mimic in which the aC is being replaced by N, and the carbonyl group is replaced by a sulfonyl group such that the peptidomimetic comprises within its backbone structure one or more [amine-NR-sulfonylonyl] units, wherein R represents the side-chain moiety of the azasulfuryl residue.
  • the azasulfuryl-containing peptidomimetic retain the ability to bind to CD36 but exhibits reduced binding to a ghrelin receptor such as GHS-R1a relative to GHRP-6.
  • the above-mentioned selective CD36 ligand has no or substantially no somatotrophic activity (e.g., has no or substantially no growth hormone releasing activity).
  • the above-mentioned selective CD36 ligand lacks binding activity to, or has low affinity for (e.g., has an IC 50 value of about 1 x 10 "5 M or less) a ghrelin receptor such as GHS-R1 a.
  • CD36 activity may be assessed by measuring CD36-dependent antiangiogenic properties, e.g., by measuring vascular sprouting of aortic rings (see WO2008/157738), by assessing inhibition of choroidal neovascularisation in vivo using the laser injury model (see WO2008/157738), by assessing anti-atherosclerotic effects in apolipoprotein E-deficient (apoE-/-) mice (see Marleau et al., FASEB J.
  • CD36-dependent antiangiogenic properties e.g., by measuring vascular sprouting of aortic rings (see WO2008/157738), by assessing inhibition of choroidal neovascularisation in vivo using the laser injury model (see WO2008/157738), by assessing anti-atherosclerotic effects in apolipoprotein E-deficient (apoE-/-) mice (see Marleau et al., FASEB J.
  • the azasulfuryl-containing peptidomimetics obtained by the above-defined method exhibit selectivity toward CD36.
  • Benzyl bromide was purchased from Aldrich® and filtered through a small plug of silica gel prior to use.
  • Fmoc-alanine (22) was purchased from GL Biochem® (Shanghai, China) Ltd.
  • DCE diichloroethane
  • TFA trifluoroacetic acid
  • 1 ,4-dioxane Fmoc-OSu
  • sulfuric acid and fe/t-butyl acetate were respectively purchased from Aldrich®, A&C Chemicals®, J. T. Baker®, GenScript® Corporation, A&C Chemicals® and Aldrich®, and used as received.
  • Anhydrous solvents [tetrahydrofuran (THF) and dichloromethane (DCM)] were obtained by passage through a solvent filtration system (GlassContour®, Irvine, CA). Ethyl acetate (EtOAc) and hexanes were purchased from Fisher Chemical® and fractionally distilled prior to use. Microwave irradiation was accomplished using a 300 MW Biotage® apparatus on the high- absorption level; temperature was monitored automatically. Flash chromatography 52 was on 230-400 mesh silica gel, and thin-layer chromatography was performed on silica gel 60 F254 plates from Merck®. Melting points were measured using a Gallankamp® apparatus and are uncorrected.
  • Accurate mass measurements were performed on a LC-MSD instrument from Agilent technologies in positive electrospray ionisation (ESI) mode at the Universite de Montreal Mass Spectrometry facility. Sodium and proton adducts ⁇ [M+Na] + and [M+H] + ⁇ were used for empirical formula confirmation.
  • W-(Boc)-Alaninyl-azasulfuiylglycinyl-D-phenylalanine fert-butyl ester (10, 243 mg, 0.50 mmol, prepared according to reference 15) was dissolved in THF (5 ml_), treated at room temperature with tetraethylammonium hydroxide (40% in H 2 0, 202 ⁇ _, 0.55 mmol) and benzyl bromide (66 ⁇ _, 0.55 mmol), stirred at room temperature for 3h, and the volatiles were evaporated to a residue, which was dissolved in DCM (10 mL), washed with 5% citric acid (1 x 10 mL), water (1 x 10 mL) and brine (1 x 10 mL), dried over MgS0 4 , filtered and evaporated.
  • fert-Butyl N-(4-fluorobenzyl)fluorenylidene carbazate (47, 2.52 g, 6.27 mmol) was treated with a solution of NH 2 OH HCI (1.7 g, 25.1 1 mmol) in pyridine (17 ml.) at 60 °C for 12 h. The volatiles were evaporated and the residue was purified by flash chromatography eluting with EtOAc:Hexane 1 :9.
  • a solution of A/-(Alloc)-alanine (12, 945 mg, 5.42 mmol, prepared according to reference 49) in THF (25 ml) was cooled to -15°C, treated slowly with /so-butyl chloroformate (700 ⁇ _, 5.42 mmol) and W-methylmorpholine (750 ⁇ _, 6.75 mmol), stirred for 15 min and treated slowly with a solution of ierf-butyl A -(4-fluorobenzyl)carbazate (13, 1.08 g, 4.42 mmol) in THF (25 ml). After stirring for 3 h at -15°C, the volatiles were evaporated to a residue, which was used without further purification.
  • Azasulfuryl tripeptide 11 (202 mg, 0.35 mmol) was dissolved in f-BuOAc, treated with cone. H 2 S0 4 (77.8 ⁇ _, 1.40 mmol), stirred at room temperature for 3 h, and the mixture was quenched with saturated NaHC0 3 (10 mL). The mixture was extracted with EtOAc (4 x 15 mL). The organic layers were combined and evaporated to a residue, which was dissolved in water (3.5 mL), cooled in an ice bath, and treated with potassium carbonate (65 mg, 0.47 mmol) followed drop-wise with a solution of Fmoc-OSu (138 mg, 0.14 mmol) in 1 ,4-dioxane (6.5 mL).
  • Fmoc-Alanine (22, 1.87 g, 6.00 mmol) was dissolved in dry THF (35 mL) at -15 °C. At -15 °C were added / ' so-butyl chloroformate (780 ⁇ _, 6.00 mmol) and 4-methylmorpholine (820 ⁇ _, 15.0 mmol). It was stirred for 15 min, and treated with a solution of ferf-butyl carbazate (0.66 g, 5.00 mmol) in dry THF (5 mL).
  • W-(Boc)Hydrazide 23 (399 mg, 0.94 mmol) was treated with TFA:DCM 1 :1 (1 mL) at room temperature for 1h. The volatiles were evaporated, the residue was dissolved in DCM and co-evaporated several times to remove TFA. The residue was partitioned between sat. NaHC0 3 (20 mL) and CHCI 3 (20 mL), and the aqueous phase was extracted with CHCI 3 (4 x 20 mL).
  • sulfamide 32a was synthesized as described for 15b. The residue was purified by flash chromatography eluting with hexane:EtOAc 3:2. The collected fractions were evaporated to a residue, which was dissolved in DCM (25 mL), washed with sat.
  • Tripeptide 33 (70 mg, 0.17 mmol) was treated with DIC (26.3 pL, 0.17 mmol) in THF (1 mL) at room temperature for 18h. The precipitate was filtered through a plastic syringe filter and the filtrate was evaporated.
  • Azasulfurylglycine peptide 40 was prepared according to reference 15. Crystals were grown from mixtures of hexanes in ethyl acetate.
  • W-iFmocJ-AT-iBocJ-D-Tryptophan [(R)-54, 1.00 g, 1.9 mmol] was dissolved in MeCN (20 mL) and treated with diethylamine (5.87 mL, 57 mmol) for 1.5 h. The volatiles were evaporated and water (25 mL) was added. The product in the aqueous phase was washed with Et 2 0 (2 x 25 mL). Sodium hydroxide (1 M, 2 mL) was then added to the aqueous phase.
  • allyl chloroformate 55, 0.301 mL, 2.82 mmol
  • sodium hydroxide 2 M, 1 mL
  • the reaction mixture was allowed to stir for an additional 30 min.
  • the aqueous phase was washed with Et 2 0 (2 x 25 mL) and acidified using 1 M HCI until pH was approx. 1.
  • the product was extracted with Et 2 0 (3 x 50 mL).
  • 2-Phenyl-2-propanol (56, 408 mg, 3 mmol, prepared according to reference 53) was dissolved in DCM (5 mL), treated with pyridine (0.36 mL, 4.5 mmol), cooled to 0 °C, and treated drop-wise with a solution of phenyl chloroformate (57, 0.51 mL, 4.06 mmol) in DCM (5 mL).
  • the cold-water bath was allowed to warm to room temperature with stirring for 18 h.
  • the reaction mixture was diluted with DCM (50 mL) and washed with 1 N HCI (50 mL), 1 M NaOH (50 mL) and water (50 mL).
  • W-(Coc)Hydrazide 52 (510 mg, 0.90 mmol) was treated with 2% of TFA in DCM (5 ml.) for 1.5 h. The volatiles were evaporated to a residue that was purified by flash chromatography eluting with a gradient of 50-80% EtOAc in hexanes containing 2% NEt 3 .
  • reaction mixture was diluted with DCM (250 mL), washed with water (2 x 100 mL), dried over MgS0 4 , filtered and evaporated to a residue, that was purified by flash chromatography eluting with 1 :4 EtOAc:hexane.
  • Ester 70 (0.92 g, 1.36 mmol) was dissolved in MeCN (16 mL), treated with diethylamine (4 mL, 38.8 mmol), and stirred at room temperature for 1.5 h. The volatiles were evaporated to a residue that was purified by flash chromatography eluting with 2:3 EtOAc:hexane containing 2% NEt 3 .
  • Methyl triflate (0.17 mL, 1.5 mmol) was added dropwise to a solution of sulfonate 3 (351 mg, 1.2 mmol) in DCM (5 mL) at 0 °C. After stirring at 0 °C for 3 h, the reaction mixture was concentrated. The residue was dissolved in MeCN (5 mL) and added dropwise to a solution of Trp(Boc)-ODmb (4; 454 mg, 1 mmol) in MeCN (5 mL) at room temperature. The reaction mixture was stirred for 18 h, and concentrated to a residue that was purified by flash chromatography eluting with 3:17 EtOAc:hexane.
  • Imidazole (5.11 g, 75.0 mmol) was dissolved in dry DCM (250 mL) in a 500 mL flamed dried flask under argon, cooled to 0 °C, treated with 4-hydroxybenzaldehyde (48, 5.00 g, 40.9 mmol), followed by ferf-butyldimethylsilyl chloride (6.78 g, 45.0 mmol), and allowed to warm to room temperature. After stirring for 18 h, the mixture was washed with water (3 x 100 mL).
  • Aldehyde 49 (3.00 g, 12.7 mmol) was dissolved in EtOH (25 ml_), cooled to 0 °C, and treated with NaBH 4 (0.96 g, 25.4 mmol). After stirring for 2 h, the solution was poured slowly into 150 mL of 1 N HCI at 0 °C. The aqueous solution was then extracted with Et 2 0 (4 x 150 ml.) and the organic phase was dried over MgS0 4, filtered and evaporated to a residue. The residue was purified by flash chromatography eluting with 4:1 hexane:EtOAc.
  • Phosphorus tribromide 35 ⁇ _, 0.38 mmol was dissolved in dry DCM (30 mL), cooled to 0 °C, and treated drop-wise with a solution of alcohol 50 (180 mg, 0.76 mmol) in dry DCM (40 mL).
  • Fmoc-Rink resins (17, 100-200 mesh, 0.64 and 1.00 mmol / g loading) were purchased respectively from NovaBiochem® (EMD Bioscience Inc., San Diego, CA, USA) and Advanced ChemTech® (Louisville, Kentucky, USA).
  • Amino acids e.g., Fmoc-Lys(Boc), Fmoc- D-Phe, Fmoc-D-Trp(Boc), Fmoc-Ala, Fmoc- and Boc-His(Trt)] were purchased from GL Biochem® (Shanghai, China) Ltd.
  • HBTU 0-Benzotriazole-A/,A/,A/ ⁇ A etramethyl-uronium-hexafluoro- phosphate
  • HOBt hydroxybenzotriazole
  • DIEA di- / ' so-propylethylamine
  • DIC di-/ ' so-propylcarbodiimide
  • TES triethylsilane
  • 4-fluorobenzyl bromide 4-methoxybenzyl bromide, 2-(bromomethyl)-naphthalene
  • 4-hydroxybenzaldehyde (48) imidazole, fert-butyldimethylsilyl chloride (TBDMSCI) and sodium borohydride, all were purchased from Aldrich® and used as received.
  • RP-HPLC-MS reverse phase high performance liquid chromatography- mass spectrometry
  • the Fmoc protecting group was removed by treating the resin with a solution of 20% piperidine in DMF, agitation for 0.5 h, resin filtration, and agitation with fresh 20% piperidine in DMF solution for another 0.5 h.
  • the resin was filtered, washed and filtered successively using 15 sec agitations with DMF (3 times), MeOH (3 times) and DCM (3 times), sequentially.
  • the resin was swollen in DMF as described above. Meanwhile, a solution of the desired Fmoc-amino acid (3.0 eq.) and HBTU (3.0 eq.) in DMF (2 mL) was stirred for 1 min, treated with DIEA (6.0 eq.), stirred for 5 min and then added to the swollen resin. The reaction mixture was shaken for 18 h at room temperature. The resin was then filtered and washed as described above, and dried in vacuo.
  • Fmoc-Protected resin (5 mg) in a 1 mL plastic filtration tube with a polyethylene filter was treated with 20% piperidine in DMF as described above. The resin was swollen and cleaved with 0.5 mL of a cocktail of TFA : H 2 0 : TES (95 : 2.5 : 2.5) for 1 h at room temperature. The resin was filtered. The filtrate was collected in a 1.5 mL Eppendorf® tube and its volume was concentrated by bubbling air through the solution. A precipitate was then produced on addition of Et 2 0 (1 mL), and collected with a centrifuge for 2 min.
  • Peptide was cleaved from the resin (100 mg) using a cocktail of TFA:H 2 0:TES (95:2.5:2.5, 2 mL) for 3 h in a cold room (4 °C).
  • the resin was filtered and washed with TFA (2 x 2 mL).
  • the filtrate was collected in a 50 mL Eppendorf tube and concentrated by bubbling air.
  • a precipitate was produced by adding Et 2 0 (50 mL) to the concentrate, and collected with a centrifuge for 5 min. The ethereal solvent was decanted. The precipitate was dissolved in H 2 0 (5 mL) and freeze-dried to a solid.
  • Fmoc-Rink resin (17, 1.25 g, 0.64 mmol / g, 0.80 mmol or 1.00 g, 1.00 mmol / g, 1.00 mmol) was swollen in DMF (8 mL) in a 12 mL plastic filtration tube with a polyethylene filter, treated with 20% piperidine in DMF (8 mL) to remove the Fmoc group as described above, and coupled to Fmoc-Lys(Boc) (respectively 1.12 g, 2.40 mmol or 1.41 g, 3.00 mmol) using HBTU (respectively 0.91 g, 2.40 mmol or 1.14 g, 3.00 mmol) and DIEA (respectively 0.83 mL, 4.80 mmol or 1.00 mL, 6.00 mL) as described in the general protocol.
  • Resin 18 (188 mg, 0.64 mmol / g, 0.12 mmol) was swollen in DMF (2 mL) in a 3 mL plastic filtration tube with a polyethylene filter. Meanwhile, a solution of tripeptide 16a (77 mg, 0.12 mmol) and HBTU (46 mg, 0.12 mmol) in DMF (2 mL) was stirred for 1 min, treated with DIEA (42 pL, 0.24 mmol), stirred for 5 min and then added to the resin. The resin mixture was shaken for 18 h at room temperature.
  • Resin 18 (264 mg, 0.42 mmol / g, 0.111 mmol) was swollen in DMF (3 mL) in a 6 mL plastic filtration tube with a polyethylene filter. Meanwhile, a solution of tripeptide 16b (87 mg, 0.166 mmol) and HOBT (23 mg, 0.166 mmol) in DMF (3 mL) was stirred for 1 min, treated with DIC (25.9 pL, 0.166 mmol), stirred for 5 min and then added to the resin. The resin mixture was shaken for 18 h at room temperature.
  • Pd(PPh 3 ) 4 (16 mg, 0.014 mmol, freshly washed with EtOH) and A/,A/-dimethylbarbituric acid (111 mg, 0.47 mmol, 7.0 eq.) in 2 mL of 3:2 DCM:DMF.
  • the resin was filtered and retreated with the same conditions for a second time for 2 h.
  • the resin was filtered, washed, treated with 0.5% sodium diethylthiocarbamate (2 mL) for 30 min, filtered and washed two more times with 0.5% sodium diethylthiocarbamate (2 mL) for 15 sec.
  • resin 20b [20b-1 , Rt 4.28 min: SunfireTM column; gradient: 5%-80% MeOH (0.1 % FA) for 7.5 min + 90% MeOH (0.1 % FA) for 2.0 min].
  • Azasulfurypeptide 21a was synthesized from resin 19a by sequential Fmoc group removals, HBTU couplings with Fmoc-D-Trp(Boc), followed by Fmoc-His(Trt) and resin cleavage using the respective general protocols described above. Analysis of a resin aliquot as described above indicated peptide 21a to be of 73% purity: Rt 13.08 min on a Gemini C18 column with a gradient of 0%-80% MeOH (0.1% FA) in water (0.1% FA) for 30.0 min, followed by 90% MeOH (0.1% FA) in water (0.1 % FA) for 10.0 min.
  • the TFA salt was purified by preparative RP-HPLC using a Gemini® 5 micron C18 110A column (Phenomenex® Inc., 250x21.2 mm, 5 ⁇ ) with a gradient of 30%-55% MeOH (0.1 % FA) in water (0.1% FA), with a flow rate of 10.0 mL / min, to afford the desired formic acid (FA) salt 21a (11.0 mg, 12%).
  • the purified product was analyzed by analytical RP-HPLC using a Gemini® 5 micron C18 110A column (Phenomenex® Inc., 150 * 4.6 mm, 5 pm) and revealed to be of >99% purity: Gradient 1 : Ri 18.95 min [5%-80% MeOH (0.1% FA) in water (0.1 % FA) for 30.0 min + 90% MeOH (0.1% FA) in water (0.1% FA) for 10.0 min]; Gradient 2: Rt 13.55 min [5%-80% MeCN (0.1% FA) in water (0.1% FA) for 30.0 min + 90% MeCN (0.1 % FA) in water (0.1% FA) for 10.0 min].
  • HRMS (ESI) m/z calculated for C 42 H 54 Ni 2 Na0 7 S [M+Na] + 893.3851 ; found 893.3832.
  • Azasulfurypeptide 21b was synthesized from resin 20b by sequential Fmoc group removals, HBTU couplings of Fmoc-D-Trp(Boc), followed by Fmoc-Ala and resin cleavage using the respective general protocols described above. Analysis of a resin aliquot as described above indicated peptide 21b to be of 79% purity: Rt 5.96 min using a Sunfire column and a gradient of 20%-80% MeOH (0.1% FA) in water (0.1 % FA) for 14 min.
  • the TFA salt was purified by preparative RP-HPLC using a Gemini 5 micron C18 110A column (Phenomenex® Inc., 250x21.2 mm, 5 pm) with a gradient of 35%-50% MeOH (0.1% FA) in water (0.1% FA), with a flow rate of 10.0 mL/min, to afford the desired FA salt 21b (6.5 mg, 23%).
  • the purified product was analyzed by analytical RP-HPLC using the Sunfire column and revealed to be of >99% purity: gradient 1 : Rt 6.79 min [20%-80% MeOH (0.1% FA) in water (0.1 % FA) for 7.5 min followed by 90% MeOH (0.1% FA) in water (0.1% FA) for 2.0 min]; Gradient 2: Rt 7.65 min [10%-80% MeCN (0.1% FA) in water (0.1% FA) for 7.5 min followed by 90% MeCN (0.1% FA) in water (0.1% FA) for 2.0 min].
  • HRMS (ESI) m/z calculated for C 39 H 5 iFNio0 7 S [M+Na]+ 845.3647; found 845.3539.
  • Resin 18 (497 mg, 1.00 mmol / g, 0.497 mmol) was swollen in DMF (2 mL) in a 3 mL plastic filtration tube with a polyethylene filter. Meanwhile, a solution of tripeptide 36 (396 mg, 0.621 mmol) and DIC (97 ⁇ , 0.621 mmol) in DMF (2 mL) was stirred for 1 min, treated with HOBt (84 mg, 0.621 mmol), stirred for 5 min and added to the resin swollen in DMF.
  • Resin 59 was synthesized as described above for resin 19b from resin 58 (116 mg, 0.42 mmol / g, 0.049 mmol), tripeptide 57 (85 mg, 0.086 mmol), DIC (13.4 ⁇ , 0.086 mmol) and HOBt (12 mg, 0.086 mmol) in DMF (2 mL.
  • Resin 37 (100 mg, 0.071 mmol) was swollen in DMF, the Fmoc protection was removed, and the resin was washed as described above.
  • resin 19b was synthesized as described above.
  • resin 19d was synthesized as described above.
  • resin 19f was synthesized as described above.
  • Azasulfurylpeptide 21a was synthesized from resin 20a by sequential Fmoc group removals, HBTU couplings of Fmoc-D-Trp(Boc), followed by Boc-His(Trt) and resin cleavage using the respective general protocols described above. Analysis of a resin aliquot as described above indicated that peptide 21a exhibited identical retention time as material prepared from azasulfuryl tripeptide 16a and revealed to be of 82% purity. His-D-Trp-Ala-AsFi4-F)-D-Phe-Lvs-NH, (21c) 21c
  • Azasulfurylpeptide 21c was synthesized from resin 20b by sequential Fmoc group removals, HBTU couplings of Fmoc-D-Trp(Boc), followed by Boc-His(Trt) and resin cleavage using the respective general protocols described above. Analysis of a resin aliquot as described above indicated peptide 21c to be of 65% purity: Rf 5.96 min using a SunfireTM column and a gradient of 5%-80% MeOH (0.1 % FA) in water (0.1 % FA) for 7.5 min followed by 90% MeOH (0.1% FA) in water (0.1% FA) for 2.0 min.
  • the TFA salt was purified by preparative RP-HPLC using a Gemini® 5 micron C18 110A column (Phenomenex® Inc., 250*21.2 mm, 5 ⁇ ) with a gradient of 20%-50% MeOH (0.1% FA) in water (0.1 % FA), with a flow rate of 10.0 mL / min, to afford the desired FA salt of 21c (1.0 mg, 3%).
  • Azasulfurylpeptide 21d was synthesized from resin 20c by sequential Fmoc group removals, HBTU couplings with Fmoc-D-Trp(Boc), followed by Boc-His(Trt) and resin cleavage using the respective general protocols described above. Analysis of a resin aliquot as described above indicated peptide 21d to be of 75% purity: Rf 5.26 min using a SunfireTM column on a gradient of 5%-80% MeOH (0.1 % FA) in water (0.1 % FA) for 7.5 min followed by 90% MeOH (0.1% FA) in water (0.1% FA) for 2.0 min.
  • the TFA salt was purified by preparative RP-HPLC using a Gemini® 5 micron C18 110A column (Phenomenex® Inc., 250*21.2 mm, 5 ⁇ ) with a gradient of 15%-45% MeOH (0.1% FA) in water (0.1 % FA), with a flow rate of 10.0 mL / min, to afford the desired FA salt of 21d (4.1 mg; 10%).
  • the purified product was analyzed by analytical RP-HPLC using the SunfireTM column and revealed to be of >99% purity: Gradient 1 : Rt 5.40 min [15%-45% MeOH (0.1 % FA) in water (0.1 % FA) for 7.5 min + 90% MeOH (0.1 % FA) in water (0.1 % FA) for 2.0 min]; Gradient 2: Rt 6.19 min [10%-30% MeCN (0.1% FA) for 7.5 min + 90% MeCN (0.1 % FA) for 2.0 min].
  • HRMS (ESI) m/z calculated for C 43 H 56 Ni 2 Na0 8 S [M+Na] + 923.3957; found 923.3936.
  • Azasulfurylpeptide 21e was synthesized from resin 20d by sequential Fmoc group removals, HBTU couplings with Fmoc-D-Trp(Boc), followed by Boc-His(Trt) and resin cleavage using the respective general protocols described above. Analysis of a resin aliquot as described above indicated peptide 21e to be of 61 % purity: Rt 5.92 min using a SunfireTM column and a gradient of 5%-80% MeOH (0.1 % FA) in water (0.1 % FA) for 7.5 min followed by 90% MeOH (0.1% FA) in water (0.1% FA) for 2.0 min.
  • the TFA salt was purified by preparative RP-HPLC using a Gemini® 5 micron C18 110A column (Phenomenex® Inc., 250*21.2 mm, 5 ⁇ ) with a gradient of 20%-50% MeOH (0.1% FA) in water (0.1 % FA), with a flow rate of 10.0 mL / min, to afford the desired FA salt of 21e (4.2 mg, 10%).
  • Azasulfurylpeptide 21f was synthesized from resin 20e by sequential Fmoc group removals, HBTU couplings with Fmoc-D-Trp(Boc), followed by Boc-His(Trt) and resin cleavage using the respective general protocols described above. Analysis of a resin aliquot as described above indicated peptide 21f to be of 70% purity: Rf 5.03 min using a SunfireTM column and a gradient of 10%-40% MeOH (0.1% FA) in water (0.1% FA) for 7.5 min followed by 90% MeOH (0.1% FA) in water (0.1% FA) for 2.0 min.
  • the TFA salt was purified by preparative RP-HPLC using a Gemini® 5 micron C18 110A column (Phenomenex® Inc., 250x21.2 mm, 5 ⁇ ) with a gradient of 20%-50% MeOH (0.1% FA) in water (0.1 % FA), with a flow rate of 10.0 mL / min, to afford the desired FA salt of 21 f (3.4 mg, 9%).
  • Azasulfurylpeptide 72 was synthesized from resin 21c by sequential Fmoc group removal, HBTU couplings of Fmoc-D-Trp(Boc), Fmoc-His(Trt), Fmoc-Ala, followed by Fmoc- Try(f-Bu), and resin (60 mg) cleavage using the respective general protocols described above. Analysis of a resin aliquot as described above indicated peptide 72 to be of 86% purity: Rf 4.98 min using a SunfireTM column and a gradient of 10%-80% MeOH (0.1% FA) in water (0.1% FA) for 7.5 min followed by 90% MeOH (0.1% FA) in water (0.1 % FA) for 2.0 min.
  • the TFA salt was purified by preparative RP-HPLC using a Gemini® 5 micron C18 110A column (Phenomenex® Inc., 250x21.2 mm, 5 pm) with a gradient of 20%-50% MeOH (0.1% FA) in water (0.1 % FA), with a flow rate of 10.0 mL / min, to afford the desired FA salt of 72 (2.5 mg, 13%).
  • the murine J774A.1 macrophage cell line was obtained from American Type Cell Collection (ATCC #TIB-67), seeded at 1.5 x 105 cells/well in DMEM containing 100U/ml_ of penicillin (Pen) and 100 ⁇ g/mL of streptomycin (Strep) on a 48-well plate (Costar® #3548), and incubated at 37 °C with 5% C0 2 . After 2 h, the medium of adhered cells was changed to DMEM-Pen/Strep containing 0.2% of bovine serum albumin (BSA), and supplemented with either the azasulfurylpeptides or [azal_ys 6 ]-GHRP-6 (43) as a negative control.
  • BSA bovine serum albumin
  • the cells were stimulated overnight with 300 ng/mL of the TLR2 ligand fibroblast- stimulating lipopeptide (R-FSL-1) (Invivogen® #L7022).
  • R-FSL-1 TLR2 ligand fibroblast- stimulating lipopeptide
  • DAN 2,3-diaminonaphtalene
  • 25 ⁇ _ of sample was incubated with 0.5 ⁇ g of DAN in a 100 ⁇ _ final volume of phosphate buffer (50 mM, pH 7.5) at room temperature in the dark. After 15 min, the reaction was stopped with 20 ⁇ _ of NaOH (2.8N) and the plate was read using a fluorescence plate reader (TECAN® Safire, ⁇ ⁇ ⁇ 0 365 nm and em 430 nm).
  • Peritoneal macrophages from C57BL/6 mice or CD36-deficient mice were harvested from sterile DMEM cell-culture medium (Wisent # 319-005-CL). Peritoneal cells were allowed to adhere for 1 h at 37°C in a 5% CO2 atmosphere, and washed twice with PBS to remove nonadherent cells. Macrophages (0.5 x 10 6 cells/well) were plated in 48-well culture plates with DMEM containing 0.2 % of bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • Macrophages were pretreated for 2 h with the azasulfurylpeptides or [aza-Lys 6 ]-GHRP-6 (43, 1 ⁇ ), before stimulation with R-FSL-1 at 300 ng/ml, lipoteichoic acid (LTA, Invivogen® #TLRL-PSLTA) at 1 pg/ml or Pam 3 CysSerLys 4 (PAMsCSK ⁇ Invivogen® #TLRL-PMS) at 100 ng/ml and interferon gamma (IFNy, R&D Systems® # 172-5201 ) at 20 ng/ml for 4 or 24 hours.
  • LTA lipoteichoic acid
  • PAMsCSK ⁇ Invivogen® #TLRL-PMS Pam 3 CysSerLys 4
  • IFNy interferon gamma
  • ELISA eBioscience® #88-7324; 88-7391
  • TNFa proinflammatory cytokine
  • MCP-1 chemokine
  • the effect on NF- ⁇ activation was assessed on cell lysates after 0, 5, 10, 15 and 30 minutes stimulation with R-FSL1 , using NF-KB p65/RelA specific ELISA-based assay (eBioscience® #85-86083).
  • the results were expressed as mean ⁇ SEM and were analyzed statistically by a one-way ANOVA with a Dunnett as a post- test. Level of significance was set at P ⁇ 0.05.
  • the reaction was stopped by diluting the mixture with 1 mL of 0.1% TFA.
  • the iodinated peptide was separated by HPLC on reverse-phase Vydac Ci 8 column with a 60 min linear gradient from 20% to 50% of acetonitrile in 0.1% TFA.
  • the fraction containing the iodinated peptide was diluted in DMEM containing 25 mM HEPES and store at -80°C.
  • J774 cells a murine macrophage cell line expressing CD36, were seeded at 125,000 cells per well in a 24-well plate and allowed to grow overnight in complete medium (DMEM-HEPES supplemented with 10% FBS and 1 % penicillin/streptomycin) at 37°C with 5% C0 2 .
  • the cells were starved 2hrs before the internalization in experimentation medium (DMEM-HEPES supplemented with 1% penicillin/streptomycin and 0.2% BSA).
  • the kinetic study of internalization was initiated by incubating the cells with 100,000 CPM of iodinated peptide in experimentation medium at 37°C.
  • A/-(Fmoc)alaninyl-azasulfuryl-phenylalaninyl-D-phenylalanine (16a) was synthesized in solution by an approach featuring alkylation of A/-(Boc)alaninyl- azasulfurylglycinyl-D-phenylalanine ferf-butyl ester (10), which was prepared according to the published procedure featuring coupling of A -(Boc)alanine hydrazide (8) and 4-nitrophenyl D- phenylalanine fert-butyl ester sulfamidate (9) 15 .
  • azasulfuryl-4-fluorophenylalanine tripeptide 16b was synthesized from carbazate 13 (Scheme 1 , see Example 1 for the synthesis of 13), 24 which was coupled to Alloc- alanine (12) using / ' so-butyl chloroformate and W-methylmorpholine. After Boc group removal using 30% trifluoroacetic acid in dichloromethane, hydrazide 14 was coupled to sulfamidate 9 under microwave irradiation to afford azasulfuryl-4-fluorophenylalanine tripeptide 15b in 41 % yield. The terf-butyl ester was finally cleaved using 50% trifluoroacetic acid in dichloromethane to give acid 16b.
  • Example 3 Diversity-oriented solid-phase azasulfurylpeptide synthesis.
  • a Percent in parentheses refers to crude purities of peptide obtained after an aliquot cleavage of resin using TFA:H 2 0:TES (95:2.5:2.5), followed by LC- S analysis using 5-80% MeOH (0.1% FA) in H 2 0 (0.1% FA) as eluent.
  • a Percent in parentheses refers to crude purities of peptide obtained after an aliquot cleavage of resin using TFA:H 2 0:TES (95:2.5:2.5), followed by LC- MS analysis using 5-80% MeOH (0.1% FA) in H 2 0 (0.1% FA) as eluent.
  • AsG peptide 38 was alkylated with benzyl bromide and tetraethylammonium hydroxide in THF to afford cleanly AsF peptide 19c, which was converted to 21a by removal of the alloc protection, sequence elongation, and cleavage.
  • the synthesized peptide was obtained in 82% crude purity, as assessed by LC-MS analysis of the residue after cleavage of an aliquot of resin, and demonstrated to have identical retention time as material made by the building block approach described above.
  • AsG tripeptide 57 was coupled using DIC and HOBt in DMF to provide pentapeptide 59.
  • Alkylation of AsG 60 with iodomethane and tetraethylammonium hydroxide in THF for 5 h gave azasulfurylalanine (AsA) in 65% conversion.
  • Alloc protecting group analysis of an aliquot of resin by LC-MS after cleavage gave a mass indicative that the Alloc was cleaved, albeit in 17% crude purity.
  • azasulfuryltripeptide 32b was achieved using an analogous method as that described for 32a with the exception of using chloroform (CHCI 3 ) instead of 1 ,2-dichloroethane (DCE) in the micro-wave assisted coupling of sulfamidate 9 and hydrazide 31a (Scheme 4).
  • CHCI 3 chloroform
  • DCE 1 ,2-dichloroethane
  • the ⁇ dihedral angles for the tripeptides 32b and 40 were respectively -55.5° and 72.5°, consistent with the preferred staggered conformation ( ⁇ 60°) found in X-ray analyses of sulfonamides, yet different from ⁇ torsion angles in the X-ray structures of azasulfuryldipeptides 41 and 42, which were -90°, and closer to the eclipsed conformation ( ⁇ 100°) of sulfonamides.
  • the ⁇ dihedral angle of the azasulfuryltripeptides 32b and 40 were respectively 105.1 ° and -107.8°, consistent with the theoretical value of ⁇ 90° predicted for diacy I hydrazines and found in X-ray structures of azapeptides. 26-3
  • the ⁇ torsion angle values of the azasulfuryltripeptides 32b and 40 were also similar (respectively, -61.4° and 51.1°).
  • the ⁇ and ⁇ dihedral angle combination of the azasulfuryltripeptides 32b (105.1°, -61.4°) and 40 (-107.8°, 51.1°) are respectively within close proximity to the ideal torsion angle values of the central residue found in normal (75°, -65°) and inverse (-75°, 65°) ⁇ -turns.
  • 32"42 azasulfuryltripeptides may have potential to exhibit biological activity by mimicking such natural turn geometry.
  • the relative binding affinities of [AsF 4 ]-GHRP-6 21a, GHRP-6 and [azaF 4 ]-GHRP-6 for CD36 were measured using surface plasmon resonance (SPR) with a His-tagged protein linked to a modified peptide monolayer. 46
  • SPR surface plasmon resonance
  • the affinity for CD36 of azasulfurylpeptide 21a (12.4 ⁇ ) was higher relative to GHRP-6 (25.6 ⁇ ), but lower than that of its azapeptide counterpart [azaF 4 ]-GHRP-6 (1.3 ⁇ ).
  • TLRs Toll-like receptors
  • azasulfurylpeptides 21b-f were examined for their potential to influence the effects of TLR2-specific ligand on the function and downstream signaling of the TLR2 receptor.
  • azasulfurylpeptides 21b-f were examined for potential to decrease the overproduction of nitric oxide (NO) induced by the TLR2 agonist fibroblast-stimulating lipopeptide (R-FSL-1) in a J774 macrophage cell line.
  • NO nitric oxide
  • Murine J774A.1 macrophage cells were exposed to azasulfurylpeptide 21b-f, or [azal_ys 6 ]-GHRP-6 (43) as negative control for 2 h, then stimulated overnight with R-FSL-1. After collection of the supernatants, the quantity of nitrite was measured in a fluorescence assay using 2,3-diaminonaphtalene ( Figure 4). Notably, azasulfurylpeptides 21c and 21 d suppressed NO production mediated by TLR2 agonist by respectively 29% and 21 %, suggesting that these ligands reduce the oxidative stress within macrophages ( Figure 3).
  • the kinetic profile of modulation of TLR2-mediated inflammation through the NF-KB pathway by azasulfurylpeptide 21c was measured in peritoneal macrophages from C57BL/6 mice. After treatment with azasulfurylpeptide (1 ⁇ ), the plated macrophages were stimulated with R-FSL-1 (300 ng/ml) and IFNy (20 ng/ml) for 0, 5, 10, 15 and 30 minutes.
  • azasulfurylpeptide 21c reduced significantly the TLR2-ligand elicited amounts of NF-KB: reduced by 11 % (P ⁇ 0.05) at 5 min, by 29% (P ⁇ 0.01 ) at 10 min and by 25% (P ⁇ 0.05) at 15 min after exposure to R-FSL-1 ( Figure 4).
  • Azasulfurylpeptides 21c-f were examined next for potential to decrease the secretion of the proinflammatory cytokine TNFa and chemokine MCP-1 downstream from NF-KB activation after induction by TLR2-specific ligands such as R-FSL-1 and lipoteichoic acid (LTA) in peritoneal macrophages.
  • TLR2-specific ligands such as R-FSL-1 and lipoteichoic acid (LTA) in peritoneal macrophages.
  • Peritoneal macrophages were harvested from C57BL/6 mice, or CD36-deficient mice as negative control, and plated in 48 well-culture plates for 1h. The cells were then treated with azasulfurylpeptide 21c-f or a negative control for 2 h prior to stimulation with the different TLR2 ligands in the presence of IFNy. The supernatant was then recovered, and ELISA assays were performed to measure the amounts of proinflammatory cytokin
  • peritoneal macrophages from C57BL/6 or CD36-deficient mice were pretreated with 1 ⁇ of azasulfurylpeptide 21c-f or 43 (negative control), 47 then stimulated with R-FSL-1 (300 ng/ml), LTA (1 g/ml) or Pam 3 CysSerLys 4 (PAMaCS Q, 100 ng/ml) and with IFNy (20 ng/ml) for 4 or 24 h.
  • R-FSL-1 300 ng/ml
  • LTA 1 g/ml
  • PAMaCShQ Pam 3 CysSerLys 4
  • IFNy 20 ng/ml
  • Pretreatment of macrophages with 21d significantly reduced secretion of TNFa. Moreover, pretreatment of macrophage with 21c significantly reduced the R-FSL-1 -induced secretion of both TNFa and MCP-1 by 20 % (P ⁇ 0.01 ) and 29 % (P ⁇ 0.05), respectively, suggesting that these ligands reduce the TLR2-induced inflammation within the macrophages ( Figures 5A and 5B).
  • azasulfurylpeptide 21c was next assessed.
  • Chronic photooxydative stress induced by blue light exposure has been validated as a causative factor for AMD by inducing lipid oxidation in the retina (57), and thus the effect of azasulfurylpeptide 21c following blue light exposure in ApoE " ' " mice was tested.
  • Triantafilou M.; Gamper, F. G.; Lepper, P. M.; Mouratis, M. A.; Schumann, C; Harokopakis, E.; Schifferle, R. E.; Hajishengallis, G.; Triantafilou, K. Lipopolysaccharides from atherosclerosis-associated bacteria antagonize TLR4, induce formation of TLR2/1/CD36 complexes in lipid rafts and trigger TLR2-induced inflammatory responses in human vascular endothelial cells. Cell. Microbiol. 2007, 9, 2030.
  • Double-bend Conformers Revealed by IRATR and Molecular Modelling J. Pept. Sci. 1997, 3, 65.

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Abstract

L''invention concerne de nouveaux peptidomimétiques contenant des azasulfuryles pouvant inhiber l'activité CD36. L'invention concerne également l'utilisation de ces peptidomimétiques contenant des azasulfuryles pour le traitement de maladies, troubles ou affections liés au CD36, notamment de maladies, troubles ou affections inflammatoires à médiation par TLR2, et des méthodes d'obtention de tels peptidomimétiques contenant un azasulfuryle.
PCT/CA2015/050832 2014-08-29 2015-08-28 Modulateurs cd36 à base d'azasulfurylpeptides et utilisations de ceux-ci WO2016029324A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2019008441A1 (fr) * 2017-07-04 2019-01-10 Intocell, Inc. Composés comprenant un lieur clivable et leurs utilisations
RU2795168C2 (ru) * 2017-07-04 2023-04-28 Интоселл, Инк. Соединения, содержащие расщепляемый линкер, и способы их применения

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MERLINO: "Design and synthesis of new urotensin-II derivatives", DOCTORAL THESIS FROM UNIVERSITA DEGLI STUDI DI NAPOLI FEDERICO II, 7 April 2014 (2014-04-07), pages 1 - 120 *
SABATINO ET AL.: "Structure-activity relationships of GHRP-6 azapeptide ligands of the CD 3 scavenger receptor by solid-phase submonomer azapeptide synthesis", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 133, 21 June 2011 (2011-06-21), pages 12493 - 12506 *
TURC OTTE ET AL.: "N-Aminosulfamide peptide mimics from aza-sulfurylglycinyl peptides: synthesis, conformation and activity", JOURNAL OF PEPTIDE SCIENCE, vol. 18, no. Supplement S1, 21 August 2012 (2012-08-21) *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019008441A1 (fr) * 2017-07-04 2019-01-10 Intocell, Inc. Composés comprenant un lieur clivable et leurs utilisations
CN111278845A (zh) * 2017-07-04 2020-06-12 尹图赛利有限公司 包含可裂解接头的化合物及其用途
RU2795168C2 (ru) * 2017-07-04 2023-04-28 Интоселл, Инк. Соединения, содержащие расщепляемый линкер, и способы их применения
US11753431B2 (en) 2017-07-04 2023-09-12 Intocell, Inc. Compounds comprising cleavable linker and uses thereof

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