Compound for inhibiting the influx of polymorphonuclear leukocytes (PMNS) in a tissue, its selection, pharmaceutical compositions and use
AssigneeFornix Biosciences N.V.
InventorsFranciscus Petrus Nijkamp, Rosswell Robert Pfister, Jeffrey Lynn Haddox, James Edwin Blalock, Matteo Villain
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Abstract
The invention relates to a compound suitable for inhibiting the influx of polymorphonuclear leukocytes (PMNs) into a tissue involved in a chronic inflammatory disease. The compound according to the invention is capable of forming a complex with N-acetyl-Pro-Gly-Pro. The invention also relates to a method of selecting such a compound, a pharmaceutical composition and an application of the compound.
Claims21
A compound suitable for inhibiting the influx of polymorphonuclear leukocytes (PMNs) into a tissue involved in a chronic inflammatory disease in a mammal, which compound, in the presence of equimolar amounts of a) N-acetyl-Pro-Gly-Pro (“N-AcPGP”), b) a compound designated as 4RTR with the formula I
- 2
- which may form a complex with N-AcPGP, and c) the compound, inhibits complex formation between N-AcPGP and 4RTR by at least 10% due to N-AcPGP being bound by the compound.
A method of screening a number of compounds with respect to their capability to inhibit the formation of a complex between 4RTR and N-AcPGP, screening occurring by means of an assay comprising a competition reaction between i) a compound A to be assayed and ii) a compound B capable of binding N-AcPGP having an equilibrium constant K of 5.10−5 M−1 or lower, compound A and compound B being in competition for the binding to a Pro-Gly-Pro (PGP)-comprising compound C, with which the compound B is able to complex, having an equilibrium constant K of 5.10−5 M−1 or lower, and wherein a thus assayed compound A is selected having an equilibrium constant K for the reaction between compound A and the PGP-comprising compound C of 10−4 M−1 or lower.
A compound suitable for inhibiting the influx of PMNs in a tissue involved in a chronic inflammatory disease in a mammal, which compound E, in the presence of an equimolar amount of N-acetyl-Pro-Gly-Pro (“N-AcPGP”), competes for binding to a PMN and inhibits the binding of N-AcPGP to the PMN by at least 10% as a result of N-AcPGP being bound by the compound, and which compound E does not induce activation of the PMN.
A method of screening a number of compounds with respect to their ability to inhibit the binding of N-AcPGP to a PMN, wherein screening occurs
- a) by using an assay comprising a competition reaction between a compound E to be assayed and a compound D for the binding to a PMN, wherein compound D is capable of competing with N-acetyl-Pro-Gly-Pro (“N-AcPGP”) for binding to a PMN and at equimolar concentrations of the compound D and N-AcPGP, inhibits the binding of N-AcPGP by at least 50%, and at equimolar concentrations of the compound E and compound D, inhibits the binding of D to the PMN by at least 10%, and
- b) by contacting the compound E with a PMN and selecting a compound E which substantially does not induce activation of the PMN.
Dependencies are inferred from the claim text.