N-terminal modifications of RANTES and methods of use
N-terminally modified RANTES derivatives are disclosed. The derivatives effectively block the inflammatory effects of RANTES, and are useful for the treatment of asthma, allergic rhinitis, atopic dermatitis, atheroma/atherosclerosis, and rheumatoid arthritis. Additionally, the compounds are useful for the treatment of HIV infection.
1. A compound of the formula:
R 1 -RANTES (2-68)
where R 1 is CH 3 —(CH 2 ) n —X—; in which
X is —C(O)—NH—CH 2 —C(O)—, —NHCH 2 —C(O)—, —ONH—CH 2 —C(O)—, —OCH 2 —CH 2 —C(O)—, —CH═CH—C(O)—, —C(O)—, or a covalent bond;
and n is an integer of 4-8;
and in which RANTES (2-68) is a polypeptide having the sequence: PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP AVVFVTRKNR QVCANPEKKW VREYINSLEM S (SEQ ID No. 2) or is a polypeptide having a variant of said sequence, the variant sequence having at least 80% sequence homology with said sequence;
wherein said compound inhibits HIV-1 R5 virus infection of PBMCs in vitro;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein n is 4 and X is —C(O)—NH—CH 2 —C(O)—.
3. The compound of claim 1 , wherein n is 5 and X is —NH—CH 2 —C(O)—.
4. The compound of claim 1 , wherein n is 7 and X is —C(O)—.
5. The compound of claim 1 , wherein n is 8 and X is a covalent bond.
6. The compound of claim 1 , wherein n is 4 and X is —ONH—CH 2 —C(O)—.
7. The compound of claim 1 , wherein n is 5 and X is —CH═CH—C(O)—.
8. The compound of claim 1 , wherein n is 4 and X is —OCH 2 —CH 2 —C(O)—.
9. A pharmaceutical composition, which composition comprises a therapeutically effective amount of a compound of the formula:
R 1 -RANTES (2-68)
where R 1 is CH 3 —(CH 2 ) n —X—; in which
X is —C(O)—NH—CH 2 —C(O)—, —NHCH 2 —C(O)—, —ONH—CH 2 —C(O)—, —OCH 2 —CH 2 —C(O)—, —CH═CH—C(O)—, —C(O)—, or a covalent bond; and n is an integer of 4-8;
and in which RANTES (2-68) is a polypeptide having the sequence:
PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP AVVFVTRKNR QVCANPEKKW VREYINSLEM S (SEQ ID No. 2) or is a polypeptide having a variant of said sequence, the variant sequence having at least 80% sequence homology with said sequence;
wherein said compound inhibits HIV-1 R5 virus infection of PBMCs in vitro;
or a pharmaceutically acceptable salt thereof;
in admixture with one or more pharmaceutically acceptable excipients.
10. The pharmaceutical composition of claim 9 , wherein N is 4 and X is —C(O)—NH—CH 2 —C(O)—.
11. The pharmaceutical composition of claim 9 , wherein N is 5 and X is —NHCH 2 —C(O)—.
12. The pharmaceutical composition of claim 9 , wherein N is 7 and X is —C(O)—.
13. The pharmaceutical composition of claim 9 , wherein N is 8 and X is a covalent bond.
14. The pharmaceutical composition of claim 9 , wherein N is 4 and X is —ONH—CH 2 —C(O)—.
15. The pharmaceutical composition of claim 9 , wherein N is 5 and X is —CH═CH—C(O)—.
16. The pharmaceutical composition of claim 9 , wherein N is 4 and X is —OCH 2 —CH 2 —C(O)—.
17. A compound of the formula:
R 1 -RANTES (2-68)
where R 1 is CH 3 —(CH 2 ) n —X—; in which
X is —C(O)—NH—CH 2 —C(O)—, —NHCH 2 —C(O)—, —ONH—CH 2 —C(O)—, —OCH 2 —CH 2 —C(O)—, —CH═CH—C(O)—, —C(O)—, or a covalent bond;
and n is an integer of 4-8;
and in which RANTES (2-68) is a polypeptide having the sequence: PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP AVVFVTRKNR QVCANPEKKW VREYINSLEM S (SEQ ID No. 2) or is a polypeptide having a variant of said sequence, the variant sequence having at least 80% sequence homology with said sequence;
wherein said compound binds to the RANTES CCR5 receptor;
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition, which composition comprises a therapeutically effective amount of a compound of the formula:
R 1 -RANTES (2-68)
where R 1 is CH 3 —(CH 2 ) n —X—; in which
X is —C(O)—NH—CH 2 —C(O)—, —NHCH 2 —C(O)—, —ONH—CH 2 —C(O)—, —OCH 2 —CH 2 —C(O)—, —CH═CH—C(O)—, —C(O)—, or a covalent bond;
and n is an integer of 4-8;
and in which RANTES (2-68) is a polypeptide having the sequence: PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP AVVFVTRKNR QVCANPEKKW VREYINSLEM S (SEQ ID No. 2) or is a polypeptide having a variant of said sequence, the variant sequence having at least 80% sequence homology with said sequence;
wherein said compound binds to the RANTES CCR5 receptor;
or a pharmaceutically acceptable salt thereof;
in admixture with one or more pharmaceutically acceptable excipients.
19. A compound of the formula:
R 1 -RANTES (2-68)
where R 1 is CH 3 —(CH 2 ) n —X—; in which
X is —C(O)—NH—CH 2 —C(O)—, —NHCH 2 —C(O)—, —ONH—CH 2 —C(O)—, —OCH 2 —CH 2 —C(O)—, —CH═CH—C(O)—, —C(O)—, or a covalent bond;
and n is an integer of 4-8;
and in which RANTES (2-68) is a polypeptide having the sequence: PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP AVVFVTRKNR QVCANPEKKW VREYINSLEM S (SEQ ID No. 2) or variant of said sequence having from 1 to 20 single amino acid deletions, insertions or substitutions relative to said sequence;
wherein said compound inhibits HIV-1 R5 virus infection of PBMCs in vitro;
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition, which composition comprises a therapeutically effective amount of a compound of the formula:
R 1 -RANTES (2-68)
where R 1 is CH 3 —(CH 2 ) n —X—; in which
X is —C(O)—NH—CH 2 —C(O)—, —NHCH 2 —C(O)—, —ONH—CH 2 —C(O)—, —OCH 2 —CH 2 —C(O)—, —CH═CH—C(O)—, —C(O)—, or a covalent bond;
and n is an integer of 4-8;
and in which RANTES (2-68) is a polypeptide having the sequence: PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP AVVFVTRKNR QVCANPEKKW VREYINSLEM S (SEQ ID No. 2) or variant of said sequence having from 1 to 20 single amino acid deletions, insertions or substitutions relative to said sequence;
wherein said compound inhibits HIV-1 R5 virus infection of PBMCs in vitro;
or a pharmaceutically acceptable salt thereof;
in admixture with one or more pharmaceutically acceptable excipients.
21. A compound of the formula:
R 1 -RANTES (2-68)
where R 1 is CH 3 —(CH 2 ) n —X—; in which
X is —C(O)—NH—CH 2 —C(O)—, —NHCH 2 —C(O)—, —ONH—CH 2 —C(O)—, —OCH 2 —CH 2 —C(O)—, —CH═CH—C(O)—, —C(O)—, or a covalent bond;
and n is an integer of 4-8;
and in which RANTES (2-68) is a polypeptide having the sequence: PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP AVVFVTRKNR QVCANPEKKW VREYINSLEM S (SEQ ID No. 2) or variant of said sequence having from 1 to 20 single amino acid deletions, insertions or substitutions relative to said sequence;
wherein said compound binds to the RANTES CCR5 receptor;
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition, which composition comprises a therapeutically effective amount of a compound of the formula:
R 1 -RANTES (2-68)
where R 1 is CH 3 —(CH 2 ) n —X—; in which
X is —C(O)—NH—CH 2 —C(O)—, —NHCH 2 —C(O)—, —ONH—CH 2 —C(O)—, —OCH 2 —CH 2 —C(O)—, —CH═CH—C(O)—, —C(O)—, or a covalent bond;
and n is an integer of 4-8;
and in which RANTES (2-68) is a polypeptide having the sequence: PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP AVVFVTRKNR QVCANPEKKW VREYINSLEM S (SEQ ID No. 2) or variant of said sequence having from 1 to 20 single amino acid deletions, insertions or substitutions relative to said sequence;
wherein said compound binds to the RANTES CCR5 receptor;
or a pharmaceutically acceptable salt thereof;
in admixture with one or more pharmaceutically acceptable excipients.