US2005208016A1PendingUtilityA1
N-terminal modification of RANTES and methods of use
Est. expirySep 3, 2017(expired)· nominal 20-yr term from priority
A61P 31/18A61P 37/08A61P 9/10A61P 29/00A61K 38/00C07K 14/523A61P 17/00
51
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 : 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: (SEQ ID NO:2) PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP AVVFVTRKNR QVCANPEKKW VREYINSLEM S or is a polypeptide having a variant of said sequence, the variant sequence having at least 80% sequence homology with said sequence; wherein the compound further comprises one or more grafted organic chain-like molecules; or a pharmaceutically acceptable salt of the compound.
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 : The compound of claim 1 , wherein said compound inhibits HIV-1 R % virus infection of PBMCs in vitro.
10 : The compound of claim 1 , wherein said compound binds to the RANTES CCR5 receptor.
11 : The compound of claim 1 , wherein RANTES (2-68) is a polypeptide having the sequence
(SEQ ID NO:2)
PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP
AVVFVTRKNR QVCANPEKKW VREYINSLEM S.
12 : The compound of claim 1 , wherein RANTES (2-68) is a polypeptide having the sequence
(SEQ ID NO:2)
PYSSDT TPCCFAYIAR PLPRAHIKEY FYTSGKCSNP
AVVFVTRKNR QVCANPEKKW VREYINSLEM S
or a variant of said sequence having from 1 to 20 single amino acid deletions, insertions or substitutions.
13 : The compound of claim 1 , wherein one or more of said grafted organic chain like molecules are PEG-based chains.
14 : The compound of claim 1 , wherein one or more of said grafted organic chain like molecules is PEG.
15 : The compound of claim 1 , wherein said grafted organic chain-like molecules are grafted at the C-terminus.
16 : A method of treating a disease state in a mammal that is alleviated by treatment with a RANTES inhibitor, which method comprises administering to the mammal in need of such treatment a therapeutically effective amount of the compound of claim 1 .
17 : The method of claim 16 , wherein the disease state is an inflammatory disease.
18 : The method of claim 17 , wherein the inflammatory disease is asthma, allergic rhinitis, atopic dermatitis, atheroma, atherosclerosis, or rheumatoid arthritis.
19 : The method of claim 9 , wherein the disease state is HIV.
20 : A composition which comprises of a compound of claim 1 in admixture with one or more pharmaceutically acceptable excipients.Cited by (0)
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