Therapeutic Agent or Prophylactic Agent for COVID-19
[Problem] To develop novel therapeutic agents for viral diseases such as coronavirus infections. [Solution] The present invention provides a therapeutic or prophylactic agent for viral diseases containing a compound with inhibitory activity against the function of Pin1 or a pharmaceutically acceptable salt thereof as an active ingredient.
1 . A therapeutic or prophylactic agent for COVID-19 containing a compound with a function of inhibiting Pin1 or a pharmaceutically acceptable salt thereof as an active ingredient.
2 . The therapeutic or prophylactic agent according to claim 1 , wherein the compound is a compound represented by the following Formula (I-I):
(wherein at least one of R 11 and R 12 is an optionally substituted polycyclic aryl group, an optionally substituted polycyclic heterocyclic group, or a group represented by the following Formula (I-II):
(wherein rings A and B respectively represent an optionally substituted monocyclic or polycyclic aryl group, and R 14 represents an optionally substituted alkylene group having 1 to 3 carbon atoms, an optionally substituted alkenylene group having 2 to 3 carbon atoms, or divalent oxy group),
if neither R 11 nor R 12 is any of the aforementioned groups, R 11 or R 12 is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted monocyclic heterocyclic group,
R 13 is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, and
X 1 is a single bond, —CO— group, —CO—O—CH 2 — group, —CO—CH 2 —O— group, —SO 2 — group, —CH 2 —CO—NH— group, —CH 2 —CO— group, —CH 2 — group, or —CO—CH 2 — group).
3 . The therapeutic or prophylactic agent according to claim 2 , wherein at least one of the R 11 and the R 12 is an optionally substituted polycyclic aryl group.
4 . The therapeutic or prophylactic agent according to claim 3 , wherein at least one of the R 11 and the R 12 is an optionally substituted naphthyl group.
5 . The therapeutic or prophylactic agent according to claim 4 , wherein the R 11 is an optionally substituted naphthyl group.
6 . The therapeutic or prophylactic agent according to any one of claims 2 to 5 , wherein the R 13 is a hydrogen atom or a methyl group.
7 . The therapeutic or prophylactic agent according to any one of claims 2 to 6 , wherein X 1 is —CO— group.
8 . The therapeutic or prophylactic agent according to claim 1 , wherein the compound is a compound represented by the following Formula (II-I):
(wherein m represents an integer from 0 to 2, n represents an integer from 0 to 1, and 0≤m+n≤2,
R 21 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group,
R 22 is an optionally substituted aryl group containing a condensed ring of three or more rings, a substituted naphthyl group, or a group represented by the following Formulae (II-II), (II-III), (II-IV), or (II-V):
(wherein a ring A represents an optionally substituted monocyclic heterocyclic group, and rings B and C respectively represent an optionally substituted monocyclic or polycyclic aryl group or heterocyclic group, and the rings A, B and C form a condensed ring);
(wherein rings D and E respectively represent an optionally substituted monocyclic or polycyclic aryl group or heterocyclic group, and R 24 represents a divalent oxy group or a carbonyl group);
(wherein rings D and E respectively represent an optionally substituted monocyclic or polycyclic aryl group or heterocyclic group);
(wherein R 25 represents 0 to 7 identical or different substituents attached to a naphthyl group, and Y 2 represents —NH— group or an alkylene group having 1 or 2 carbon atoms),
R 23 is 0 to 7 identical or different substituents attached to a naphthyl group, and
X 2 is a single bond, —CH 2 — group, or —NH— group).
9 . The therapeutic or prophylactic agent according to claim 8 , wherein the R 22 is a group represented by the following Formula (II-II):
(wherein a ring A represents an optionally substituted monocyclic heterocyclic group, rings B and C respectively represent an optionally substituted monocyclic or polycyclic aryl group or heterocyclic group, and the rings A, B and C form a condensed ring).
10 . The therapeutic or prophylactic agent according to claim 8 or 9 , wherein the m is 1, and the n is 0.
11 . The therapeutic or prophylactic agent according to any one of claims 8 to 10 , wherein the R 21 is a hydrogen atom.
12 . The therapeutic or prophylactic agent according to any one of claims 8 to 11 , wherein the X 2 is a single bond.
13 . The therapeutic or prophylactic agent according to claim 1 , wherein the compound is a compound represented by the following Formula (III-I):
(wherein m represents an integer from 0 to 2, n represents an integer from 0 to 2, and 0≤m+n≤3,
a ring A is an optionally substituted monocyclic aromatic ring or heterocycle,
X 3 is a single bond, —NH— group, —NH—CO— group, —O—CO— group, —CH 2 —S—CH 2 — group, —CH 2 —S—(CH 2 ) 2 —S— group, or —NH—R 34 — group (R 34 is an alkylene group having 1 to 5 carbon atoms, or an alkenylene group having 2 to 5 carbon atoms),
Y 3 is a single bond, —NH— group, —CO— group, —SO 2 — group, —O—CO— group, —CO—NR 35 — group (R 35 represents a hydrogen atom, or an optionally substituted alkyl group having 1 to 5 carbon atoms), —O—R 36 — group (R 36 represents an optionally substituted alkylene group having 1 to 5 carbon atoms, or an optionally substituted alkenylene group having 2 to 5 carbon atoms), —NR 35 —R 36 — group, —S—R 36 — group, —CO—R 36 — group, —SO 2 —R 36 — group, —NR 35 —CO—R 36 — group, —R 36 —NR 35 —CO— group, an optionally substituted alkylene group having 1 to 6 carbon atoms, or an optionally substituted alkenylene group having 2 to 6 carbon atoms,
Z 3 is a hydrogen atom, an optionally substituted amino group, or an optionally substituted amine,
if the Z 3 is the optionally substituted amine, the X 3 and the Z 3 form a ring,
R 31 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group,
R 32 is an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl group, or a group represented by the following Formula (III-II):
(wherein rings B and C respectively represent an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted cycloalkyl group, R 37 represents, a single bond, —O— group, —CO— group, —NH— group, —SO 2 — group, —CO—NH— group, an optionally substituted alkylene group having 1 to 3 carbon atoms, an optionally substituted alkenylene group having 2 to 3 carbon atoms, —S—R 38 — group (R 38 represents an optionally substituted alkylene group having 1 to 2 carbon atoms), —CO—R 38 — group, —O—R 38 — group, or —SO 2 —R 38 — group, and any of the ring B, ring C and R 37 is attached to the Y 3 ), and
R 33 is 0 to 4 identical or different substituents).
14 . The therapeutic or prophylactic agent according to claim 13 , wherein the m is 1, and the n is 0.
15 . The therapeutic or prophylactic agent according to claim 13 or 14 , wherein the X 3 is —NH—CO— group, or —O—CO— group.
16 . The therapeutic or prophylactic agent according to any one of claims 13 to 15 , wherein the ring A is a benzene ring.
17 . The therapeutic or prophylactic agent according to any one of claims 13 to 16 , wherein the R 32 is an optionally substituted polycyclic aryl group, or an optionally substituted polycyclic heterocyclic group.
18 . The therapeutic or prophylactic agent according to any one of claims 13 to 17 , wherein the Z 3 is a hydrogen atom.
19 . The therapeutic or prophylactic agent according to any one of claims 13 to 18 , wherein the Y 3 is a single bond, —CH 2 — group, or —CH 2 —O— group.
20 . The therapeutic or prophylactic agent according to any one of claims 13 to 19 , wherein the R 31 is a hydrogen atom.
21 . The therapeutic or prophylactic agent according to claim 1 , wherein the compound is a compound represented by the following Formula (IV-I):
(wherein a ring A represents an optionally substituted monocyclic or polycyclic aromatic ring or heterocycle,
R 41 represents an optionally substituted polycyclic aromatic ring or a group represented by any of the following Formulae (IV-II) to (IV-V):
(wherein a ring B represents an optionally substituted monocyclic heterocycle, rings C and D independently represent an optionally substituted monocyclic or polycyclic aromatic ring, heterocycle or cyclic hydrocarbon, and the rings B, C and D form a condensed ring);
(wherein a ring E represents an optionally substituted monocyclic heterocycle, a ring F represents an optionally substituted monocyclic or polycyclic aromatic ring, heterocycle or cyclic hydrocarbon, and the rings E and F form a condensed ring);
(wherein rings G and H respectively represent an optionally substituted monocyclic or polycyclic aromatic ring or heterocycle);
(wherein a ring I represents an optionally substituted monocyclic aromatic ring or heterocycle, a ring J represents an optionally substituted monocyclic or polycyclic aromatic ring, heterocycle or cyclic hydrocarbon, the rings I and J form a condensed ring, and R 46 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group);
R 42 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group;
R 43 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;
R 44 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group;
R 45 represents 0 to 3 identical or different substituents attached to a benzene ring;
X 4 represents a single bond, an alkylene group having 1 or 2 carbon atoms, —O— group, —CH 2 —O— group, —CH 2 —NH—CO— group, or —CH 2 —NH—CO—O—CH 2 — group; and
Y 4 represents a single bond or an alkylene group having 1 or 2 carbon atoms).
22 . The therapeutic or prophylactic agent according to claim 21 , wherein the ring A is an optionally substituted polycyclic aromatic ring or heterocycle.
23 . The therapeutic or prophylactic agent according to claim 22 , wherein the ring A is a ring represented by the following Formula (IV-VI):
(wherein A 1 , A 2 , and A 3 independently represent a carbon atom or a nitrogen atom, and a ring K represents an optionally substituted monocyclic or polycyclic aromatic ring, heterocycle or cyclic hydrocarbon).
24 . The therapeutic or prophylactic agent according to claim 23 , wherein all of A 1 , A 2 , and A 3 are a carbon atom.
25 . The therapeutic or prophylactic agent according to any one of claims 21 to 24 , wherein the R 41 is preferably a group represented by the following Formula (IV-II):
(wherein a ring B represents an optionally substituted monocyclic heterocycle, rings C and D independently represent an optionally substituted monocyclic or polycyclic aromatic ring, heterocycle or cyclic hydrocarbon, and the rings B, C and D form a condensed ring).
26 . The therapeutic or prophylactic agent according to any one of claims 21 to 25 , wherein the R 42 is a hydrogen atom.
27 . The therapeutic or prophylactic agent according to any one of claims 21 to 26 , wherein the R 43 is a hydrogen atom.
28 . The therapeutic or prophylactic agent according to any one of claims 21 to 27 , wherein the R 44 is a hydrogen atom.
29 . The therapeutic or prophylactic agent according to any one of claims 21 to 28 , wherein the X 4 is a single bond.
30 . The therapeutic or prophylactic agent according to any one of claims 21 to 29 , wherein the Y 4 is a single bond.
31 . A method for screening therapeutic or prophylactic agents for COVID-19, comprising steps of:
A) acquiring a library of Pin1 inhibitors by measuring their activity of inhibiting the function of Pin1 using a cell-free assay for measuring cis-to-trans conversion of a phosphorylated serine/threonine-proline motif contained in a substrate peptide; and
B) measuring ability to inhibit proliferation of SARS-CoV-2 virus of compounds identified as Pin1 inhibitors in the step A using a cell-based assay for measuring increases in viral components.
32 . A therapeutic or prophylactic agent for COVID-19 containing the Pin1 inhibitors identified by the screening method according to claim 31 or pharmaceutically acceptable salts thereof as an active ingredient.
33 . The therapeutic or prophylactic agent according to any one of claims 1 to 30 and 32 , further containing one or more active ingredients of at least one or more other drugs selected from drugs classified as therapeutic or prophylactic agents for coronavirus infections.
34 . The therapeutic or prophylactic agent according to any one of claims 1 to 30 , 32 , and 33 for treating or preventing coronavirus infections in combination with at least one or more other drugs selected from drugs classified as therapeutic or prophylactic agents for coronavirus infections.
35 . Use of the therapeutic or prophylactic agent according to any one of claims 1 to 30 , 32 , and 33 for manufacture of a medicament for treating or preventing coronavirus infection.
36 . A method of treating COVID-19, comprising administering to a subject in need thereof a therapeutically effective amount of the therapeutic or prophylactic agent according to any one of claims 1 to 30 , 32 , and 33 .