Modulators of fpr1 and methods of use thereof

A C1-C6, C1-C4 technology, applied to medical preparations containing active ingredients, pharmaceutical formulas, metabolic diseases, etc.

Pending Publication Date: 2022-07-29
BIOFRONT THERAPEUTICS (BEIJING) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The annual incidence of malignant glioma is about 6 cases per 100,000 population, and there is currently no effective treatment

Method used

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  • Modulators of fpr1 and methods of use thereof
  • Modulators of fpr1 and methods of use thereof
  • Modulators of fpr1 and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0193] Example 1. Synthesis of Exemplary Compounds

[0194] Compounds selected from the group consisting of formulae I, IIa, IIb, III, IV, V, VI and VII, compounds 1 to 4, their tautomerism can be prepared according to standard chemical practice or as described herein (including the synthetic schemes below) and in The compounds of the present disclosure are made as described in the description of the isomers, deuterated derivatives of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing compounds.

[0195] Using compounds 1 and 2 as representative examples, methods for preparing compounds of formula I include general reaction procedures as described in Scheme 1 .

[0196] Compounds 1 and 2

[0197] Racemic-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethyl)phenyl)- 4,5-Dihydro-6H-pyrrolo[3,4-c]isoxazol-6-one

[0198] (Compound 1)

[0199] Racemic-3-(2-hydroxy-5-methylphenyl)-5-(tetrahydro-2H-pyran-4-yl)-4-(4-(tr...

Embodiment 2

[0229] Example 2. In vitro assay for detection and measurement of modulation of FPR1-mediated calcium signaling by compounds 1 to 4

[0230] As shown in the illustrative examples in Table 2, the effects of compounds of the present disclosure on modulating FPR1-mediated cellular signaling were measured by monitoring changes in cellular calcium levels. The following ranking criteria were used to unambiguously report the dose-response of the examples shown: ***(IC 50 ≤100nM);**(IC 50 ≥100 to ≤1000nM); *(IC 50 ≥1000 to ≤10,000 nM); N.D. - not detected.

[0231] Expression of human or mouse FPR1 in 293T cells

[0232] The coding DNA sequences (CDS) of human FPR1 (NM_001193306) and mouse FPR1 (NM_013521) were cloned and inserted into the lentiviral vector GV367 (vector information: http: / / www.genechem.com. cn / index / supports / tool_search.html?keywords=GV367). 293T cells were cultured in H-DMEM supplemented with 10% FBS and 1% penicillin-streptomycin (PS) at 37°C in a 5% CO2 incub...

Embodiment 3

[0237] Example 3. In vivo preclinical efficacy of intracerebral hemorrhage (ICH) mouse model

[0238] The efficacy of the compounds of the present disclosure in protecting brain damage and improving brain function following stroke and / or brain injury was demonstrated in experiments described below using Compound 1 as a representative compound in an experimental ICH mouse model.

[0239] Preparation of experimental mouse ICH model

[0240] using a mouse model of intracerebral hemorrhage (ICH) to illustrate the protective benefit of compounds of the present disclosure, and figure 1 The procedure to prepare this model is depicted. ICH was induced in C57 B / L6 male mice by injection of autologous blood or collagenase as previously described (Lauer et al., Circulation 124:1654-1662 (2011); Rynkowski et al., Nat. Protoc. 3:122- 128 (2008)). Mice were anesthetized using isoflurane inhalation and fixed on a stereotaxic frame. A hole was drilled on the right side of the skull 2.3 mm...

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Abstract

The present disclosure provides compounds of Formula I, compositions comprising the same, and methods of using the same, including use in the treatment of diseases, disorders, or conditions mediated by signaling of formyl peptide receptor 1 (FPR1).

Description

technical field [0001] The present disclosure relates to compounds that are useful in the treatment of diseases. More specifically, the present disclosure relates to binding to formyl peptide receptors (FPRs) such as FPR1 to modulate their activity in order to reduce or eliminate disproportionate FPR-mediated signaling (which is a range of diseases including, for example, central Compounds for the underlying pathogenesis of diseases or disorders of the nervous system (CNS), such as stroke, traumatic brain injury (TBI), glioblastoma and glioblastoma). Background technique [0002] Restoring body homeostasis after injury or pathogen infection is essential to ensure the survival of the organism. Physiological wound healing and innate immune responses are initiated by the release of soluble mediators from invasive pathogens or injured lesions. The temperature-regulated interacting repair process involves, for example, many chemokines, cytokines, acute phase proteins, infiltrat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04A61P25/00A61P35/00A61P25/28A61P25/16A61P25/08A61P21/00A61P25/04A61P3/10A61P7/02A61P9/10A61K31/4162
CPCC07D498/04A61P25/00A61P35/00A61P25/28A61P25/16A61P25/08A61P21/00A61P25/04A61P3/10A61P7/02A61P9/10A61P9/00
Inventor T·马Z·黄F·史
Owner BIOFRONT THERAPEUTICS (BEIJING) CO LTD
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