Polypeptide having mmp2-inhibitory effect

A substituted polypeptide represented by formula [I′]:

• or a pharmaceutically acceptable salt thereof,
• wherein
• AA1 represents:
• Asp,
• β-Asp, β-(d)-Asp, γ-Glu, or γ-(d)-Glu;
• AA2 represents one group selected from the group consisting of:
• Ala,
• a group represented by any of formulas [IV-7], [IV-8], [IV-9], [IV-11], [IV-12], and [IV-13]:
• a group represented by formula [IV-27]:
• Pro, and a group represented by any of formulas [II-1] and [II-2]:
• wherein RAA2 represents hydroxy or amino;
• AA1 and AA2 may be taken together to form a structure represented by formula [IV-32]:
• AA3 represents one group selected from the group consisting of:
• Val, Leu, Ile, a group represented by formula [IV-2]:
• Phe, Trp,
• Tyr, Lys, a group represented by any of formulas [IV-3], [IV-4], and [IV-5]:
• and
• a group represented by formula [IV-9]:
• AA4 represents one group selected from the group consisting of:
• a single bond,
• Gly, (d)-Ala, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile,
• Pro, (d)-Pro,
• (N-Me)Phe, (d)-Phe,
• (N-Me)Tyr, (d)-Tyr,
• (N-Me)Ser, (d)-Ser, homoSer, (d)-Thr,
• Met, (N-Me)Met,
• (N-Me)Asp, Glu, (N-Me)Glu, (d)-(N-Me)Glu, homoGlu,
• (N-Me)Asn,
• (N-Me)Arg, (d)-Arg,
• a group represented by any of formulas [IV-7], [IV-9], and [IV-13]:
• Lys, and (N-Me)Lys,
• wherein if AA4 represents Lys, then
• the amino in the side chain of the Lys is optionally substituted with C2-16 alkylcarbonyl terminally-substituted with carboxy;
• AA5 represents one group selected from the group consisting of:
• a single bond,
• Ala, a group represented by formula [IV-1]:
• a group represented by any of formulas [IV-27], [IV-28], and [IV-29]:
• Pro, (d)-Pro, β-homoPro, homoPro, a group represented by formula [II-1′]:
• Phe, His,
• Thr,
• Arg, (d)-Arg,
• a group represented by any of formulas [IV-7], [IV-9], and [IV-13]:
• Lys, (d)-Lys,
• β-Ala, (N-Me)-β-Ala, GABA, Ape, Acp,
• a group represented by any of formulas [III-6] to [III-13]:
• and
• a group represented by any of formula [IV-25] and [IV-26]:
• W1 represents -L1- or -L1′-L1″-;
• wherein
• L1 represents a single bond;
• and
• L1′ represents one group selected from the group consisting of:
• a single bond,
• β-Ala, GABA, (N-Me)GABA, Ape, Acp,
• a group represented by any of formulas [III-6] to [III-13]
• and
• a group represented by any of formulas [IV-23] and [IV-24]:
• and
• L1″ represents one group selected from the group consisting of:
• a single bond,
• Gly, (N-Me)Gly,
• Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile,
• a group represented by formula [IV-27]:
• Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe,
• His, (d)-His, Trp, (N-Me)Trp, (d)-Trp,
• Tyr, (N-Me)Tyr, (d)-Tyr,
• (d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr,
• Cys, (d)-Cys, Met, (N-Me)Met,
• (N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu,
• Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln,
• Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit,
• a group represented by any of formulas [IV-7], [IV-9], [IV-10], and [IV-13]:
• Lys, (N-Me)Lys, (d)-Lys, a group represented by formula [IV-14]:
• β-Ala,
• β-Asp, β-(d)-Asp, and
• a group represented by any of formulas [III-6] and [III-7]:
• wherein if L1″ represents Lys or (d)-Lys, then
• the amino in the side chain of the Lys or (d)-Lys is optionally substituted with a group represented by formula [VII-1]:
• FAN-AAN5-AAN4-AAN3-AAN2-AAN1- [VII-1]
• wherein
• FAN represents C2-16 alkylcarbonyl terminally-substituted with carboxy;
• AAN5 represents:
• a single bond,
• Arg, (d)-Arg,
• Lys, (d)-Lys,
• γ-Glu, or
• a group represented by formula [IV-24]:
• AAN4 represents:
• a single bond,
• Arg, (d)-Arg,
• Lys, (d)-Lys, or
• a group represented by formula [IV-24]:
• AAN3 represents:
• a single bond,
• Arg, (d)-Arg,
• Lys, (d)-Lys,
• γ-Glu, or
• a group represented by formula [IV-24]:
• AAN2 represents:
• a single bond, or
• (d)-Lys;
• and
• AAN1 represents:
• a single bond, or
• (d)-Lys;
• wherein if L1″ represents by Glu and AA3 represents Lys, then
• the compound represented by formula [I′] may be taken together with L3 attached to each of functional groups in the side chains of the two amino acids to form a cyclic structure, as represented by formula [I′-α]:
• wherein the L3 represents Gly, β-Ala, or GABA;
• LN1 represents the formula —C(═O)— or the formula —S(═O)2—;
• LN2 represents:
• a single bond,
• C1-3 alkanediyl,
• C2-3 alkenediyl,
• ethynediyl,
• the formula —O—,
• the formula —C(═O)—, the formula —C(═O)—NH—, or
• triazolediyl;
• L2 represents a single bond;
• ring A represents an aromatic ring or a heteroaromatic ring;
• RA1 and RA2 each independently represent:
• a hydrogen atom,
• a halogen atom,
• C1-6 alkyl, or
• C1-6 alkoxy;
• ring B represents:
• aryl or heteroaryl;
• RB1, RB2, and RB3 each independently represent:
• a hydrogen atom,
• carbamoyl,
• cyano,
• a halogen atom,
• C1-6 alkyl optionally substituted with one hydroxy, halo C1-6 alkyl,
• C1-6 alkoxy optionally substituted with one hydroxy, halo C1-6 alkoxy,
• C1-6 alkylcarbonyl,
• C1-6 alkylcarbonylamino,
• mono C1-6 alkylaminocarbonyl, di C1-6 alkylaminocarbonyl, wherein the alkyl in each of the mono C1-6 alkylaminocarbonyl and the di C1-6 alkylaminocarbonyl is optionally substituted with one group selected from the group consisting of hydroxy, carboxy, carbamoyl, and amino,
• C1-6 alkylsulfonyl, or
• aryl;
• WC is a single bond or a linker consisting of one to three amino acids, wherein the one to three amino acids forming the linker are same or different and each selected from the group consisting of:
• Gly,
• Pro,
• Arg, (d)-Arg,
• Lys, (d)-Lys,
• β-Ala, GABA, and Ape,
• wherein if Lys or (d)-Lys is included in the group represented by WC, then
• the amino in the side chain of the Lys or (d)-Lys is optionally substituted with:
• C2-16 alkylcarbonyl terminally-substituted with carboxy,
• Lys, wherein the amino in the side chain of the Lys is optionally substituted with C2-16 alkylcarbonyl terminally-substituted with carboxy, or
• (d)-Lys, wherein the amino in the side chain of the (d)-Lys is optionally substituted with C2-16 alkylcarbonyl terminally-substituted with carboxy;
• and
• RC is:
• the formula —OH, the formula —NH2,
• C1-6 alkylamino, wherein the C1-6 alkyl of the C1-6 alkylamino is optionally substituted with one group selected from the group consisting of hydroxy, amino, C1-6 alkoxy, and four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom, or
• four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom;
• wherein the four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom is optionally substituted with one group selected from the group consisting of hydroxy, amino, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one carbamoyl;
• and two carbon atoms in the four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom are optionally crosslinked with C1-4 alkanediyl.