WO2016190331A1 - Inhibiteur d'une infection par le vih - Google Patents

Inhibiteur d'une infection par le vih Download PDF

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WO2016190331A1
WO2016190331A1 PCT/JP2016/065395 JP2016065395W WO2016190331A1 WO 2016190331 A1 WO2016190331 A1 WO 2016190331A1 JP 2016065395 W JP2016065395 W JP 2016065395W WO 2016190331 A1 WO2016190331 A1 WO 2016190331A1
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compound
hiv
yir
mmol
group
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玉村　啓和
雄樹 廣田
優 苛原
渉 野村
哲夫 鳴海
修三 松下
吉村　和久
恵嘉 原田
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国立大学法人東京医科歯科大学
国立大学法人熊本大学
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Priority to JP2017520727A priority Critical patent/JP6710376B2/ja
Publication of WO2016190331A1 publication Critical patent/WO2016190331A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems

Definitions

  • the present invention relates to a novel compound having an HIV infection inhibitory effect. More particularly, the present invention relates to a novel CD4 mimic compound that can block entry of HIV cells into host cells.
  • HIV Human immunodeficiency virus
  • AIDS Human immunodeficiency virus
  • AIDS Human immunodeficiency syndrome
  • HIV includes HIV-1 and HIV-2, and HIV-1 is classified into subtypes A to K. HIV-1 is common in the Western Hemisphere, Europe, Asia, and Central / Southern / Eastern Africa, and HIV-2 is common in Western Africa. HIV-2 is less contagious than HIV-1, which has many cases of infection, and the prevalent areas are limited, so the development of anti-HIV drugs and AIDS vaccines is mainly targeted at HIV-1. .
  • HIV-1 is a type of retrovirus.
  • the mature virus has a spherical shape with a diameter of 100-110 nm, and there are two copies of a single-stranded RNA genome, a reverse transcriptase, a nuclease containing a nuclease, and an envelope surrounding it (Fig. 1). ).
  • coat proteins gp120 and gp41 exist in the form of a trimer, which is a CD4, CXCR4, CD4, CXCR4, It binds specifically to CCR5 and plays an important role in the entry of HIV into host cells.
  • Multi-drug combination therapy (highly active anti-retroviral therapy: ⁇ ⁇ ⁇ ⁇ ⁇ HAART) has been established, but there are few invasion inhibitors that inhibit HIV entry into cells. Only fulavilide and maraviroc are clinically applied as CCR5 inhibitors. However, these drugs can inhibit the growth of the virus, but cannot be killed, and therefore require regular life-long drug administration. Therefore, there is a problem of the risk of accumulation of side effects due to long-term administration and high treatment costs. Furthermore, since HIV easily mutates, the emergence of drug-resistant viruses has become a major problem, and vaccine development is also difficult.
  • the first step of HIV-1 entry into the host cell is the interaction between HIV-1 coat protein gp120 and host cell surface protein CD4 (first receptor). With this interaction, the structure of gp120 changes greatly, exposing a region called the V3 loop. Next, the interaction between this V3 loop and the second receptor (co-receptor, CCR5 or CXCR4) exposes gp41 to the surface, penetrates the host cell membrane, enters the host cell via membrane fusion ( Figure 2).
  • NBD-556 having an action of inhibiting the invasion was reported by HIV-1 syncytium formation inhibition screening (Non-patent Document 1).
  • NBD-556 has also attracted attention as a small molecule CD4 mimic (mimic) compound because it can bind to the Phe43-cavity of gp120, the CD4 interaction site, and induce structural changes in gp120. References 2-4).
  • NBD-556 has problems such as low anti-HIV activity, high cytotoxicity, and low water solubility.
  • Non-Patent Documents 5 to 8 structure-activity relationship research using NBD-556 as a lead compound has been actively conducted.
  • HAR-171 is a compound synthesized with the intention of interacting with two amino acids Val430 and Asp368 present near the entrance of the Phe43-cavity based on the co-crystal structure of NBD-556 and gp120.
  • Val430 is a compound synthesized with the intention of interacting with two amino acids Val430 and Asp368 present near the entrance of the Phe43-cavity based on the co-crystal structure of NBD-556 and gp120.
  • hydrophobic interaction with Val430 was confirmed, but no significant interaction with Asp368 was observed.
  • the present inventors acted on the Phe43-cavity that is the binding site of the first receptor CD4 to inhibit the interaction between gp120 and CD4.
  • This inhibition strategy is not only a mechanism of action different from the conventional one, but also it is difficult to induce drug resistance to HIV-1 and can aim to develop a new drug that suppresses HIV effectively and continuously.
  • cyclohexyl groups of monocyclohexyl compounds have hydrophobic interactions with Val430 and guanidino groups are introduced into compounds that have electrostatic interactions with the carboxy group of the Asp368 side chain.
  • a compound having an anti-HIV activity superior to that of a conventionally known compound and low cytotoxicity could be obtained.
  • the obtained compound has a synergistic anti-HIV effect when used in combination with a neutralizing antibody that specifically recognizes the V3 loop exposed during the HIV entry mechanism.
  • the present invention can provide a novel HIV infection inhibitor having high anti-HIV activity, low cytotoxicity, and capable of producing synergistic anti-HIV activity when used in combination with a neutralizing antibody.
  • the compound of the present invention has higher hydrophilicity than NBD-556 and is suitable for administration in an aqueous preparation such as an injection.
  • the HIV infection inhibitor of the present invention can be widely applied to HIV that is known to cause mutations at a high frequency.
  • FIG. 1 schematically shows the structure of HIV-1.
  • 1 schematically shows the mechanism of HIV-1 entry into a host cell.
  • the activity enhancement effect when the compound of the present invention is used in combination with the neutralizing antibody KD-247 is shown.
  • A. YIR-819 (Compound 23), B. YIR-802 (Compound 29), C. YIR-821 (Compound 26), D. YIR-329 (Compound 11), E. NBD-556 The result of the docking simulation of the compound of this invention and Phe43-cavity of HIV-1 is shown.
  • the result of the docking simulation of the compound of the present invention (YIR-819, Compound 23) and the Phe43-cavity of HIV-1 is shown.
  • the present invention relates to the general formula (I): Or a salt thereof.
  • X is a halogen atom selected from Cl, Br, and F.
  • the halogen atom X is preferably in the meta or para position relative to the other substituent. Particularly preferably, X is Cl.
  • A is an alkylene group having 1 to 5 carbon atoms.
  • A is preferably an alkylene group having 2 to 4 carbon atoms, particularly preferably ethylene.
  • B is of the formula (II): (Wherein R 1 and R 2 are each independently an alkylene group having 1 to 5 carbon atoms which may contain a carbonyl group) It is group which has.
  • a preferred compound is a compound of formula (I) or a salt thereof, wherein X is Cl, A is ethylene, and B has the structure of formula (II).
  • a particularly preferred compound is a compound of formula (I) or a salt thereof, wherein X is Cl, A is ethylene and R 1 and R 2 are both ethylene, for example Compound 29 shown (YIR-802).
  • B is the formula (III): (Wherein R 3 is an alkylene group having 1 to 5 carbon atoms which may contain a carbonyl group) It is group which has.
  • a preferred compound is a compound of formula (I) or a salt thereof, wherein X is Cl, A is ethylene, and B has the structure of formula (III).
  • a particularly preferred compound has the formula where X is Cl, A is ethylene, and R 3 is —CO— (CH 2 ) n —, where n is 1 to 4.
  • B is the formula (IV): It is group which has.
  • a preferred compound is a compound of formula (I) or a salt thereof, wherein X is Cl, A is ethylene and B has the structure of formula (IV), for example Compound 20 (YIR-737)
  • the compound of the general formula (I) can form a salt with an inorganic or organic base at the guanidino group moiety.
  • the salt is not particularly limited, but is preferably a pharmaceutically acceptable salt.
  • hydrochloride, sulfate, phosphate, succinate, fumarate, mesylate, tosylate, bromide Hydronate, acetate, trifluoroacetate and the like can be preferably used.
  • Scheme 1-3 shows a method for synthesizing monocyclohexyl 4-aminopiperidine.
  • compound 1 phthalimide
  • methyl vinyl ketone is allowed to act in the presence of a base to form compound 2 (Michael adduct), followed by acetal protection of the carbonyl group, followed by hydrazine decomposition to compound 4 (ring (Scheme 1).
  • compound 6 (imine) is formed by allowing cyclohexanone to act on compound 4, then adding BF 3 ⁇ OEt 2 complex as a Lewis acid and reacting under microwave irradiation, compound 6 (cyclized product) ). Then, 2-cyclohexyl-4-oxopiperidine (Compound 7) was obtained by deprotecting the acetal group under acidic conditions (Scheme 2).
  • Scheme 4 shows a method for synthesizing a monocyclohexyl CD4 mimic derivative.
  • YIR-329 (Compound 11) was reacted with 1H-pyrazole-1-carboxyamidine hydrochloride to obtain guanidinized YIR-720 (Compound 15). The resulting compound was purified by HPLC and isolated as the trifluoroacetate salt (Scheme 5).
  • YIR-703 (Compound 17) was obtained by reacting YIR-329 (Compound 11) with 2- (N- (tert-butoxycarbonyl) amino) -O- (4-methylphenylsulfonyl) ethanol. (Scheme 7).
  • YIR-329 (compound 11) was allowed to act on bromoacetonilolyl to induce YIR-631 (compound 18), and then the nitrile group was reduced using LiAlH 4 to yield YIR-723 (compound 19 ) The resulting compound was purified by HPLC and isolated as the trifluoroacetate salt (Scheme 8).
  • YIR-723 (compound 19) was reacted with 1H-pyrazole-1-carboxyamidine hydrochloride to obtain guanidinized YIR-737 (compound 20). The resulting compound was purified by HPLC and isolated as the trifluoroacetate salt (Scheme 9).
  • YIR-723 (compound 19) was condensed with N- (tert-butoxycarbonyl) glycine using a condensing agent, and then the Boc group was deprotected with trifluoroacetic acid to obtain YIR-818 (compound 22). . Thereafter, 1H-pyrazole-1-carboxyamidine hydrochloride was allowed to act to obtain guanidinized YIR-819 (Compound 23). The obtained YIR-818 (Compound 22) and YIR-819 (Compound 23) were purified by HPLC and isolated as a trifluoroacetate salt (Scheme 10).
  • YIR-723 (compound 19) was condensed with N- (tert-butoxycarbonyl) -5-aminovaleric acid using a condensing agent, and then the Boc group was deprotected with trifluoroacetic acid to yield YIR-820 (compound 25) Thereafter, 1H-pyrazole-1-carboxyamidine hydrochloride was allowed to act to obtain guanidinized YIR-821 (Compound 26). The obtained YIR-820 (Compound 25) and YIR-821 (Compound 26) were purified by HPLC and isolated as a trifluoroacetate salt (Scheme 11).
  • YIR-723 (Compound 19) is reacted with bromoacetonitrile to give YIR-738 (Compound 27), and then LiAlH 4 is used to reduce the nitrile group to yield YIR-801 (Compound 28). Obtained. Thereafter, 1H-pyrazole-1-carboxyamidine hydrochloride was allowed to act to obtain guanidinized YIR-802 (Compound 29). The obtained YIR-801 (Compound 28) and YIR-802 (Compound 29) were purified by HPLC and isolated as a trifluoroacetate salt (Scheme 12).
  • a monocyclohexyl type compound YIR-329 (compound 11) having a chloro group at the para position. It was found to have superior anti-HIV activity than the compound HAR-171.
  • molecular modeling analysis of YIR-329 (compound 11) suggested that the cyclohexyl group had a hydrophobic interaction with Val430.
  • a derivative synthesized with the intention of improving electrostatic interaction with Asp368 based on YIR-329 (compound 11) is a compound in which a guanidino group is introduced on the piperidine nitrogen atom, and further has anti-HIV activity. It has been found to improve.
  • Molecular modeling analysis of the resulting compound suggested that the introduced guanidino group formed an electrostatic interaction with the carboxy group of the Asp368 side chain.
  • the obtained compound was also evaluated for cytotoxicity.
  • the compound represented by the above general formula (I) or a salt thereof has high anti-HIV activity and low cytotoxicity, and more surprisingly, it can act synergistically in combination with an anti-HIV antibody. It was found.
  • the compounds of the present invention are expected to be capable of hydrophobic interaction with Val430 and electrostatic interaction with Asp368 or Asp474, and to achieve moderate water solubility for application to pharmaceutical formulations
  • the piperidine ring has a structure in which one cyclohexyl group and a guanidino group are bonded via a linker (spacer) having a certain length.
  • the water solubility of the compound of the present invention can be described by, for example, the retention time in high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the inventors of the present invention performed HPLC measurement on the compound of the present invention under the following conditions, and obtained the following results.
  • Eluent Two-component gradient mode using water and acetonitrile (both containing 0.1% TFA)
  • Column 5C18-AR-II (4.6 x 250 mm) (manufactured by Nacalai Tesque)
  • Detection wavelength 254 nm
  • the water solubility of the compound of the present invention can be expressed using a distribution coefficient indicating the fat solubility of the compound, for example, a clogP value which is a LogP value calculated by calculation.
  • a clogP value which is a LogP value calculated by calculation.
  • the present inventors set the miLogP (Molinspiration calculated logP) value for the compounds of the present invention using the program Molinspiration property engine v2014.11 provided by Molinspiration property calculation service (http://www.molinspiration.com/). Calculated.
  • the miLogP value is a numerical value corresponding to the clogP value.
  • the miLogP value of YIR-737 (Compound 20) is 2.16
  • the miLogP value of YIR-819 (Compound 23) is 1.76
  • the miLogP value of YIR-821 (Compound 26) is 2.31
  • the YIR-802 (Compound 29)
  • the miLogP value was 1.05.
  • the miLogP value of the compound of the present invention suitable as an HIV infection inhibitor is within the range of about 1 to 2.5.
  • the compound of the present invention or a salt thereof can competitively inhibit the binding between the Phe43-cavity of HIV gp120 and CD4.
  • the structural changes in gp120 caused by the compounds of the invention or their salts are not the same as the changes caused by the interaction with CD4, but expose the V3 loop. Since subsequent binding to the co-receptor does not occur, entry of HIV into the host cell can be inhibited. Accordingly, the present invention provides an HIV infection inhibitor comprising the compound of the present invention or a salt thereof as an active ingredient.
  • the compound of the present invention or a salt thereof can be administered as it is as an HIV infection inhibitor, but in addition to this active ingredient, carriers, excipients, preservatives, oxidative stability usually used in pharmaceutical compositions An agent or the like can be added as appropriate and administered as a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition for treating or preventing HIV infection, comprising the above-described HIV infection inhibitor.
  • the HIV infection inhibitor and pharmaceutical composition of the present invention can be administered orally and parenterally, for example, oral; administration by intravenous, intramuscular, transdermal, subcutaneous, intradermal, intraperitoneal injection or infusion. However, it is not particularly limited. A person skilled in the art can appropriately determine a suitable administration route for the administration of the HIV infection inhibitor and the pharmaceutical composition of the present invention.
  • the dose of the HIV infection inhibitor of the present invention to a human depends on the age, weight, symptoms, etc. of the patient to be administered, and is not particularly limited. For example, 100 ⁇ g / kg body weight to 100 mg / kg body weight per day is preferable. Can be in the range of 500 ⁇ g / kg body weight to 50 mg / kg body weight, more preferably 1 mg / kg to 30 mg / kg body weight.
  • HIV-infection inhibitor of the present invention can be used alone, it is also intended to be used in combination with other anti-HIV drugs having an inhibitory action by different mechanisms.
  • Other anti-HIV drugs include, but are not limited to, reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and the like.
  • anti-HIV infection inhibitor and the other anti-HIV agent can be included in the same or different pharmaceutical compositions.
  • Administration of the HIV infection inhibitor of the present invention and other anti-HIV drugs may be simultaneous, sequential or completely different.
  • the administration route of the HIV infection inhibitor of the present invention and other anti-HIV drugs may be the same or different.
  • the HIV-infection inhibitor of the present invention is also intended to be used in combination with an antibody specific for HIV. Although it is not particularly limited as an antibody, it has become clear that the HIV-infection inhibitor of the present invention causes a structural change in gp120 by binding to HIV and exposes the V3 loop. It is preferred to use antibodies, particularly neutralizing monoclonal antibodies specific for the V3 loop of HIV and functional fragments thereof.
  • KD-247 (generic name: suvizumab), which is currently undergoing clinical trials, is a representative monoclonal antibody against the V3 loop of HIV. Can be mentioned.
  • KD-247 generic name: suvizumab
  • the present invention provides the above-mentioned HIV infection inhibitor or the above-mentioned pharmaceutical composition, characterized by being administered in combination with an anti-HIV antibody.
  • the anti-HIV antibody is a neutralizing antibody specific for the V3 loop on the HIV-1 surface.
  • the administration of the HIV infection inhibitor of the present invention and the anti-HIV antibody may be simultaneous, continuous or completely different. Moreover, the administration route of the HIV infection inhibitor of the present invention and the anti-HIV antibody may be the same or different.
  • a Cosmosil 5C 18 -ARII column (4.6 ⁇ 250 mm, Nacalai Tesque, Inc., Kyoto, Japan) was used for HPLC analysis and a linear gradient of CH 3 CN containing 0.1% (v / v) trifluoroacetic acid.
  • JASCO PU-2089 plus JASCO Corporation, Ltd., Tokyo, Japan
  • Preparative HPLC was performed using a Cosmosil 5C 18 -ARII column (20 ⁇ 250 mm, Nacalai Tesque, Inc.) with JASCO PU-2087 plus (JASCO Corporation, Ltd., Tokyo, Japan), 0.1% (v / v )
  • the flow rate was 7 cm 3 min ⁇ 1 using an appropriate gradient of CH 3 CN solution containing trifluoroacetic acid.
  • the microwave reaction was performed in a Biotage Microwave Reaction Kit (sealed vial) of Initiator (trademark) (manufactured by Biotage).
  • Ceric ammonium nitrate (5.22 g, 9.51 mmol) was added to a solution of compound 9 (1.2 g, 3.17 mmol) in CH 3 CN / H 2 O (23.8 / 7.92 mL). The reaction mixture was stirred at room temperature for 14 hours, then ceric ammonium nitrate (3.48 g, 6.34 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 7.5 hours, then quenched with 3 M aqueous HCl (10.6 mL, 10 eq) at 0 ° C. and extracted with CH 2 Cl 2 .
  • the aqueous phase was basified with 5 M aqueous NaOH (12.7 mL, 20 eq), then filtered through celite and washed with AcOEt. Extraction with AcOEt followed by drying of the organic phase with Na 2 SO 4 and concentration under reduced pressure afforded the title compound 10 (407 mg, 76% yield) as a yellow oil.
  • N- (tert- butoxycarbonyl) -5-amino valeric acid (216 mg, 0.994 mmol) in DMF (3.32 mL) solution of, HOBt ⁇ H 2 O (254 mg, 1.66 mmol), EDCI ⁇ HCl (318 mg, 1.66 mmol), compound 19 (130 mg, 0.332 mmol) and NEt 3 (0.397 mL, 2.32 mmol) were added at 0 ° C.
  • the reaction mixture was stirred at room temperature for 36 hours, then quenched with saturated aqueous NaHCO 3 solution at 0 ° C. and extracted with CHCl 3 .
  • Example 2 [Activity evaluation] The various novel compounds synthesized in Example 1 were evaluated for anti-HIV activity, cytotoxicity, and ability to induce structural change using the following methods. The cells and antibodies used were obtained as described in K. Yoshimura et al., J. Virology, Aug. 2010, p.7558-7568.
  • HIV-1 cYTA48P strain infectious clonal virus prepared by the present inventors by replacing virus env from HIV patients with NL43 env
  • TZM-bl cells NIH AIDS Reagent Program (https: //www.aidsreagent) obtained from .org / Index.cfm).
  • TZM-bl cells are indicator cells that have CD4 / CCR5 / CXCR4 on their surface and luciferase is expressed by HIV infection.
  • This cell contains the ⁇ -galactosidase gene linked to the HIV-1 LTR sequence, and when infected with HIV-1, the transcription activator Tat is expressed from the infected HIV-1 tat gene.
  • ⁇ -galactosidase is expressed by Tat acting on the promoter region of LTR. Enzyme cleavage occurs when a substrate is added to produce galactose and luciferin, so the number of cells infected with HIV-1 is measured by detecting the amount of chemiluminescence emitted by luciferase being oxidized by luciferase using a luminometer. be able to.
  • TZM-bl cells (1 ⁇ 10 4 cells) were cultured with 100TCID 50 cYTA48P strain and a dilution series inhibitor (a compound of the present invention or a control compound). After 48 hours of culture, measure the ⁇ -galactosidase activity using the luminometer ARVO (PerkinElmer) according to the instructions for Beta-Glo TM Assay Reagent (Promega) and compare the sensitivity of anti-HIV entry inhibitors did.
  • the IC 50 value is the concentration at which HIV-1 inhibits 50% of the cytopathogenicity of PM1 / CCR5 cells (CCR5 highly expressing T cells donated by Dr. Yosuke Maeda, Kumamoto University).
  • HIV-1 JR-FL strain persistently infected PM1 cells treated with CD4 mimic derivatives HIV-1 JR-FL strain provided by Prof. Yoshio Koyanagi, Kyoto University Virus Research Institute, to PM1 cells obtained from NIH AIDS Reagent Program
  • the degree of the structural change of gp120 on the surface of the persistently infected cell line established by the present inventors by infecting the cells was evaluated.
  • CD4i antibody 4C11, a monoclonal antibody established by the inventor's group known to specifically bind to the site exposed when gp120 undergoes a structural change (CD4-inducing site), and further A structural change of gp120 can be detected using a goat-derived anti-human IgG antibody (secondary antibody) labeled with fluorescein isothiocyanate (FITC).
  • FITC fluorescein isothiocyanate
  • the fluorescence intensity (mean fluorescent intensity: MFI) was measured by fluorescence activated cell sorting (FACS) analysis, and the degree of structural change of gp120 was quantified from the amount of CD4i antibody (4C11) binding.
  • relative FACS ([MFI of CD4 mimic derivative]-[MFI of 4C11]) / ([NBD-556 MFI]-[4C11 MFI])
  • the background noise is eliminated by subtracting the MFI for each 4C11 from each MFI.
  • Example 2-1 Activity evaluation of monocyclohexyl CD4 mimic derivatives
  • the compounds having different aromatic ring structures were compared and evaluated for anti-HIV activity, cytotoxicity and ability to induce structural change (Table 1).
  • the aromatic ring unit in the CD4 mimic derivative having a monocyclohexyl type piperidine structure is most suitable to have a chloro group in the para position.
  • -It was decided to fix to the chloro body.
  • a compound having a bromo group or a fluoro group at the para position is expected to have the same activity.
  • Example 2-2 Activity evaluation of amino-type monocyclohexyl CD4 mimic derivatives
  • the monocyclohexyl CD4 mimic derivative (YIR-329, Compound 11) had a decreased cytotoxicity but a lower anti-HIV activity than NBD-556 (Table 1). From the docking simulation of YIR-329 (compound 11) and gp120, hydrophobic interaction with Val430 was observed, but no significant interaction with Asp368 was observed (data not shown). Therefore, it was examined whether the interaction with Asp368 could be formed by modifying the piperidine nitrogen atom of YIR-329 (Compound 11).
  • Example 2-3 Activity evaluation of guanidino-type monocyclohexyl CD4 mimic derivative
  • Example 2-3 Activity evaluation of guanidino-type monocyclohexyl CD4 mimic derivative
  • Example 2-4 Activity evaluation of other types of monocyclohexyl CD4 mimic derivatives
  • the derivatives having other types of functional groups obtained in Example 1 were also evaluated for anti-HIV activity and cytotoxicity in the same manner as described above (Table 4).
  • YIR-802 (compound 29), YIR-819 (compound 23), and YIR-821 (compound 26), which are the compounds of the present invention, even at concentrations that show little activity with KD-247 alone. )
  • the inhibitory activity was enhanced, and a synergistic inhibitory action of the compound of the present invention and the anti-HIV antibody was shown. This means that when the compound of the present invention and an anti-HIV antibody are used in combination, high inhibitory activity can be brought about with a small amount of antibody.
  • Example 4 [Comparison of interaction modes by docking simulation] Based on the co-crystal structure of NBD-556 and Phe43-cavity (PDB: 3TGS), the docking simulation of the compound of the present invention and Phe43-cavity was conducted using MOE, and the binding mode was examined focusing on the piperidine ring site did. The interaction mode was compared between YIR-821 (Compound 26), which showed the best anti-HIV activity, and YIR-329 (Compound 11) and NBD-556 as comparative compounds (FIG. 4).
  • YIR-821 (compound 26), which is a compound of the present invention, is a novel CD4 mimic compound capable of effectively interacting with both Val430 and Asp368, and greatly improves the interaction with Asp368. It is thought that it contributes to the improvement of HIV activity.
  • the HIV infection inhibitor of the present invention targets a mechanism different from the conventional mechanism of HIV entry into the host cell, and is a drug repertoire for resisting the emergence of drug-resistant viruses in multidrug therapy. Can expand.
  • the HIV infection inhibitor of the present invention exhibits a synergistic effect with an anti-HIV monoclonal antibody, the amount of antibody required for treatment can be reduced, and the cost for treatment can be reduced.

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Abstract

La présente invention a pour but de fournir un inhibiteur d'une infection par le VIH qui peut agir par l'intermédiaire d'un mécanisme d'action qui est différent de ceux des médicaments anti-VIH classiques, induisant rarement une résistance aux médicaments et pouvant inhiber durablement et efficacement le VIH. L'invention concerne un composé représenté par la formule générale (I) ou un de ses sels. Le composé, selon la présente invention, possède une forte activité anti-VIH, ainsi qu'une faible cytotoxicité, et peut fournir une activité synergique lorsqu'il est utilisé en association avec un anticorps neutralisant anti-VIH.
PCT/JP2016/065395 2015-05-25 2016-05-25 Inhibiteur d'une infection par le vih WO2016190331A1 (fr)

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