High-affinity small molecule formylpeptide receptor ligands from screening of combinatorial mixture-based libraries

Patent metadata

Field	Value
Publication number	US-10048272-B2
Application number	US-201615013102-A
Country	US
Kind code	B2
Filing date	Feb 2, 2016
Priority date	Feb 7, 2013
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

The present invention provides novel methods and assays for high-throughput screening of combinatorial libraries to identify FPR1 and/or FPR2 ligands (e.g., agonists and/or antagonists), preferably FPR1 agonists and/or FPR2 antagonists, by positional scanning deconvolution.
The invention also provides novel FPR1 and FPR2 ligands (e.g, agonists and antagonists), related pharmaceutical compositions and methods of treating FPR1 and FPR2-related disorders.

First claim

What is claimed is:

1. A method of modulating formyl peptide receptor-1 (FPR1) or formyl peptide receptor-2 FPR2 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as set forth in FIG. 1 EX 3 , FIG. 1 EX 4 or FIG. 2 EX 5 herein, or a pharmaceutically acceptable salt or enantiomer thereof.

2. The method of claim 1 , wherein the subject suffers from amyloidosis, Alzheimer's disease, a prion disease, HIV, a cancer or an inflammatory disorder.

3. The method of claim 2 , wherein the subject suffers from HIV and the compound is optionally administered in combination with an additional anti-HIV agent.

4. The method of claim 2 , wherein the subject suffers from a cancer and the compound is optionally administered with an additional anti-cancer agent.

5. The method according to claim 1 wherein said compound is

a compound of FIG. 1 EX 4 , or a pharmaceutically acceptable salt or stereoisomer thereof.

6. The method according to claim 1 wherein said compound is

or a pharmaceutically acceptable salt thereof.

7. The method according to claim 2 wherein said subject suffers from cancer.

8. The method according to claim 7 wherein said cancer is selected from the group consisting of squamous-cell carcinomas, adenocarcinomas, hepatocellular carcinomas, renal cell carcinomas, leukemias; lymphomas, melanomas; myeloproliferative diseases; sarcomas, tumors of the central nervous system and germ-line tumors.

9. The method according to claim 7 wherein said cancer is selected from the group consisting of bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, testicular cancer, thyroid cancer, Burkitt's lymphoma, Non-Hodgkin's lymphoma; Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, Schwannomas, thyroid cancer, astrocytoma, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas.

10. The method according to claim 5 wherein said compound is

or a pharmaceutically acceptable salt or stereoisomer thereof.

Assignees

• Stc Unm
• Torrey Pines Inst For Molecular Studies

Inventors

• Edwards Bruce S
• Sklar Larry A
• Pinilla Clemencia
• Houghten Richard A
• Appel Jon R
• Giulianotti Marc A
• Medina-Franco Jose

Classifications

• G16C20/60

  In silico combinatorial chemistry · CPC title

• C07C275/28

  having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton · CPC title

• G16B35/00

  ICT specially adapted for in silico combinatorial libraries of nucleic acids, proteins or peptides · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K31/17

  having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64) · CPC title