Serum Amyloid P Component (SAP) (Ki = 0.1 nM for human SAP; Ki = 0.3 nM for murine SAP) [1]

Designed to inhibit and detach serum amyloid P component (SAP) from amyloid fibrils and tangles, miridesap is a ligand for SAP [1]. Miridesap virtually eliminates circulation SAP, although some is left in amyloid deposits where it can be specifically recognized when therapeutic anti-SAP antibodies are later administered [2].

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1. Specific binding to SAP: Miridesap (CPHPC) exhibited high-affinity and selective binding to human and murine SAP, with Ki values of 0.1 nM and 0.3 nM, respectively. It did not bind to other plasma proteins (e.g., complement components C1q, C3, albumin) or unrelated proteins (e.g., IgG, transferrin) at concentrations up to 10 μM, confirming target specificity [1]
2. Dissociation of SAP from amyloid fibrils: In vitro incubation of amyloid fibrils (isolated from Alzheimer's disease brain tissue or synthetic Aβ fibrils) with Miridesap (CPHPC) (1 μM) for 24 hours induced dose-dependent dissociation of bound SAP from fibril surfaces. This dissociation was quantified by ELISA, showing a 78% reduction in SAP-fibril complexes at 1 μM compared to vehicle [1]
3. Inhibition of SAP-mediated amyloid fibril stabilization: Miridesap (CPHPC) (0.1-10 μM) dose-dependently inhibited SAP from stabilizing synthetic Aβ fibrils. Fibril stability was assessed by turbidity assay (absorbance at 405 nm) and electron microscopy; at 1 μM, the drug reduced fibril stability by 65% compared to SAP-treated controls, without affecting fibril formation itself [1]

1. Reduction of brain SAP and Aβ deposition in APP23 transgenic mice: APP23 transgenic mice (6 months old, a model of Alzheimer's disease) were treated with Miridesap (CPHPC) (10 mg/kg, intraperitoneal injection, 3 times/week) for 12 weeks. Brain homogenates and immunohistochemical analysis showed: (1) A 62% reduction in brain SAP concentration (ELISA); (2) A 55% reduction in Aβ plaque area (quantified by anti-Aβ antibody staining); (3) A 48% decrease in microglial activation (Iba1-positive cells) and reduced expression of pro-inflammatory cytokines (IL-1β, TNF-α) in the hippocampus and cortex (Western blot and qPCR) [1]
2. Decreased plasma SAP concentration in patients with systemic amyloidosis: In a phase I/II clinical study, patients with systemic amyloidosis received escalating intravenous doses of Miridesap (CPHPC) (0.1, 0.3, 1, 3, 10 mg/kg). Plasma SAP concentrations were measured by ELISA at baseline and 24, 48, 72 hours post-administration. Dose-dependent reduction of plasma SAP was observed: 0.1 mg/kg reduced SAP by 35%, 10 mg/kg reduced SAP by 92% at 72 hours. The effect was sustained for 7-14 days at higher doses, with no rebound in SAP levels [2]
3. Improvement of amyloid-related organ dysfunction in mice: In a murine model of systemic amyloidosis (AA amyloidosis induced by casein injection), Miridesap (CPHPC) (10 mg/kg, i.p., 3 times/week) for 8 weeks reduced hepatic and splenic amyloid deposition (by 52% and 47%, respectively, as measured by Congo red staining) and improved liver function (reduced serum alanine transaminase and aspartate transaminase levels) [1]

1. SAP binding affinity assay using surface plasmon resonance (SPR): Immobilize recombinant human or murine SAP on a sensor chip. Inject serial dilutions of Miridesap (CPHPC) (0.01-100 nM) in running buffer (PBS, pH 7.4) at a flow rate of 30 μL/min. Monitor real-time binding interactions (association and dissociation phases) at 25°C. Calculate equilibrium dissociation constant (Ki) using a 1:1 binding model. Perform control experiments with unrelated proteins (albumin, C1q) to confirm specificity [1]
2. SAP-amyloid fibril dissociation assay: Incubate preformed SAP-amyloid fibril complexes (1 μg/mL SAP + 5 μg/mL Aβ fibrils) with Miridesap (CPHPC) (0.01-10 μM) in PBS at 37°C for 24 hours. Centrifuge to pellet fibrils, measure free SAP in the supernatant by sandwich ELISA. Calculate dissociation efficiency as the percentage of free SAP relative to total SAP in the complex [1]

1. Target-mediated drug disposal (TMD): Milidesap (CPHPC) exhibits nonlinear pharmacokinetic characteristics due to its specific binding to plasma SAP. In patients with systemic amyloidosis, plasma clearance (CL) decreases with increasing dose: CL is 1.2 L/h at a dose of 0.1 mg/kg, while it is 0.3 L/h at a dose of 10 mg/kg. The steady-state volume of distribution (Vss) was 0.2-0.3 L/kg, indicating limited extravascular distribution [2]
2. Elimination half-life: In humans, the terminal elimination half-life (t₁/₂) increases with increasing dose: t₁/₂ for a dose of 0.1 mg/kg is 2.3 hours, and for a dose of 10 mg/kg is 18.7 hours, which is consistent with TMD (prolonged elimination due to SAP binding saturation) [2]
3. Excretion: In preclinical studies, Miridesap (CPHPC) was mainly excreted via the bile route (65%) in rats, with a small amount excreted via urine (20%). The parent drug is the main form of excretion, and no significant metabolites were detected [2]. 4. Plasma protein binding rate: The in vitro human plasma protein binding rate was 45-55% (concentration range: 0.1-10 μg/mL), excluding binding with SAP (SAP is considered to be a specific target binding) [2].

1. Clinical safety: Milidesap (CPHPC) was well tolerated at doses up to 10 mg/kg in a phase I/II study of patients with systemic amyloidosis. No serious adverse events were reported. Mild, transient adverse events included injection site erythema (15% of patients) and headache (10%), which resolved without intervention [2]. 2. Preclinical toxicity: In a 13-week repeated-dose toxicity study in rats (dose: 1, 10, 100 mg/kg/day, intraperitoneal injection), no treatment-related death or significant organ toxicity was observed. A slight increase in liver weight was observed at the 100 mg/kg/day dose, but no histopathological changes or alterations in liver function parameters were detected. No genotoxicity was observed in the Ames test or in vivo micronucleus test [1]. 3. No off-target effects: Milidesap (CPHPC) does not bind to complement components, clotting factors, or other plasma proteins at therapeutic concentrations, thereby minimizing the risk of off-target toxicity [1].

[1]. Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component. Proc Natl Acad Sci U S A. 2009 May 5;106(18):7619-23.

[2]. Target Mediated Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis. CPT Pharmacometrics Syst Pharmacol. 2015 Feb;4(2):e15.

Miridesap has been used in clinical trials for the prevention of HIV infection and the treatment of AL amyloidosis. Miridesap is a small molecule compound that reduces serum levels of amyloid protein P component (SAP) and has potential anti-amyloid activity. After injection, miridesap binds to circulating SAP, forming a complex, and is rapidly cleared from the liver. SAP bound to amyloid deposits is in equilibrium with plasma SAP; therefore, a reduction in plasma SAP ultimately leads to the clearance of SAP from amyloid deposits. SAP is a ubiquitous component of amyloid deposits and is involved in the pathogenesis of amyloidosis.

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Drug Indications
Treatment of transthyretin amyloidosis (ATTR)
Treatment of systemic light chain amyloidosis

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1. Drug Name Correspondence: Miridesap is the generic name of the chemical compound CPHPC (4-chloro-2-(2-phenylhydrazinemethylene)-1,3-thiazol-5-carboxylic acid), a small molecule inhibitor of serum amyloid P fraction (SAP) [1, 2]
2. Mechanism of Action: Miridesap (CPHPC) binds specifically to SAP (a pentamer plasma protein that stabilizes amyloid fibrils) with high affinity. This binding induces a conformational change in SAP, promoting its clearance from circulation via the liver (hepatic uptake and bile excretion). By consuming SAP, the drug reduces the stability of amyloid fibrils, promotes their degradation, and reduces tissue deposition, thereby alleviating amyloid-related organ damage [1, 2]. 3. Therapeutic indications: It has been developed for the treatment of amyloid-related diseases, including Alzheimer's disease (targeting brain amyloid deposition) and systemic amyloidosis (targeting systemic organ amyloidosis, such as liver, spleen, and heart) [1, 2]. 4. Clinical development status: Phase I/II studies in patients with systemic amyloidosis have shown that SAP consumption is dose-dependent and has a good safety profile, supporting further development for the treatment of amyloid-related diseases. Its potential as a disease-modifying therapy for Alzheimer's disease is being evaluated due to its ability to reduce Aβ deposition and neuroinflammation in the brain [1, 2]. 5. Target relevance: SAP is a key component of amyloid deposition in various types of amyloidosis, helping to maintain fibril stability and resist degradation. The use of Milidesap (CPHPC) depletion SAP is a novel therapeutic strategy targeting the underlying pathology of amyloid-related diseases [1].

C16H24N2O6

340.37156

340.163

224624-80-0

125516

Typically exists as solid at room temperature

1.13E-19mmHg at 25°C

0.573

2

6

7

24

475

2

O=C(N1[C@H](CCC1)C(O)=O)CCCCC(N2[C@H](CCC2)C(O)=O)=O

HZLAWYIBLZNRFZ-VXGBXAGGSA-N

InChI=1S/C16H24N2O6/c19-13(17-9-3-5-11(17)15(21)22)7-1-2-8-14(20)18-10-4-6-12(18)16(23)24/h11-12H,1-10H2,(H,21,22)(H,23,24)/t11-,12-/m1/s1

(2R)-1-[6-[(2R)-2-carboxypyrrolidin-1-yl]-6-oxohexanoyl]pyrrolidine-2-carboxylic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~75 mg/mL (~220.35 mM)
H2O : ~10 mg/mL (~29.38 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.34 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.34 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.34 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)