Peptidomimetic compounds as immunomodulators
The present invention relates to novel peptidomimetic compounds as therapeutic agents capable of inhibiting the programmed cell death 1 (PD1) signalling pathway. The invention also relates to derivatives of the therapeutic agents. The invention also encompasses the use of the said therapeutic agents and derivatives for treatment of disorders via immunopotentiation comprising inhibition of immunosuppressive signal induced due to PD-1, PD-L1, or PD-L2 and therapies using them.
1. A compound of Formula (I):
wherein;
R 1 is hydrogen, —OR 6 , —OC(O)R 6 , halogen, cyano, or hydroxyalkyl;
R 1 ′ is hydrogen or alkyl;
both R a and R a ′ is hydrogen; or together represent an oxo (═O) group or a thioxo (═S) group;
both R b and R b ′ is hydrogen; or together represent an oxo (═O) group or a thioxo (═S) group;
R 2 and R 3 independently are hydrogen, optionally substituted alkyl or optionally substituted acyl;
R 4 and R 4 ′ independently are hydrogen, optionally substituted alkyl or optionally substituted acyl;
R 6 is hydrogen or optionally substituted alkyl;
‘n’ is an integer selected from 1 or 2;
R c is hydroxyl or amino;
R 5 is —C(═X)—Am 1 —R 7 ;
wherein, X is O or S;
Am 1 is an amino acid residue Ser, Asp, Ala, Ile, Phe, Trp, Glu, or Thr; wherein the amino acid residue is optionally substituted with an alkyl or an acyl group;
R 7 is an alpha carboxylic group of Am 1 which is in free acid, ester or in amide form; wherein the amide nitrogen is optionally substituted with hydroxyl or amino;
or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein R 1 is —OH, —OCH 3 or —OCOCH 3 .
3. The compound according to claim 1 , wherein R 1 ′, R 4 and R 4 ′ are hydrogen.
4. The compound according to claim 1 , wherein R 5 is —C(═O)—Am 1 —R 7 , wherein Am 1 is selected from Ser, Thr, Asp, Trp, Ile or Phe; and R 7 is same as defined in claim 1 .
5. The compound according to claim 1 , wherein the amino acid Am 1 is either D or L-amino acid.
6. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (IA):
wherein, R 1 , R 2 , R 3 , R 4 , R 5 and ‘n’ are same as defined in claim 1 .
7. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (IB):
wherein, R 1 , R 2 , R 3 , R 4 , X, Am 1 , R 7 and ‘n’ are same as defined in claim 1 .
8. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (IE):
wherein, R 1 , R 1 ′ R 2 , R 3 , R 4 , R 4 ′, R b , R b ′, R 7 , Am 1 , X and ‘n’ are same as defined in claim 1 .
9. A compound of a structure that is
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or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising at least one compound according to claim 1 and/or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
11. The pharmaceutical composition of claim 10 further comprising at least one additional pharmaceutical agent wherein the said additional pharmaceutical agent is an anticancer agent, chemotherapy agent, or antiproliferative compound.