CGRP receptor ( Ki = 0.027 nM )
Rimegepant hemisulfate (BMS-927711, BHV-3000) is a potent, competitive, and selective antagonist of the human calcitonin gene-related peptide (CGRP) receptor with ki of 0.027 nM.

Rimegepant hemisulfate (BMS-927711, BHV-3000) is a potent, competitive, and selective antagonist of the human calcitonin gene-related peptide (CGRP) receptor with ki of 0.027 nM.

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BMS-927711 demonstrated potent binding affinity for the human CGRP receptor with a Ki of 0.027 ± 0.009 nM, as determined by inhibition of ¹²⁵I-CGRP binding to SK-N-MC cell membranes.[1]
In a functional assay using SK-N-MC cells, BMS-927711 inhibited CGRP-stimulated cAMP production with an IC50 of 0.14 ± 0.01 nM, acting as a full, competitive antagonist.[1]
The compound showed a low level of inhibition against a panel of eight recombinant human CYP isoforms, with IC50 values ≥20 μM for all except CYP3A4 (IC50 = 17 μM).[1]
BMS-927711 exhibited no significant off-target liabilities in a panel of 45 receptor, ion channel binding, and enzyme activity assays.[1]
In vitro cardiovascular safety assessments showed that at 10 and 30 μM, BMS-927711 caused less than 30% inhibition of the hERG potassium channel alpha subunit expressed in HEK-293 cells, and had no significant effect on L-type sodium or calcium channels expressed in these cells.[1]
The compound was not mutagenic in an exploratory Ames study.[1]
BMS-927711 had good permeability in the parallel artificial membrane permeability assay (PAMPA), with values of 190 and 320 nm/sec at pH 5.5 and 7.4, respectively.[1]
The crystalline solubility of BMS-927711 was 50 μg/mL.[1]
The human plasma protein unbound fraction (fu) for BMS-927711 was 6.9%.[1]
The human liver microsomal stability half-life (HLM T1/2) for BMS-927711 was 83 minutes.[1]

In vivo efficacy [1]
A novel noninvasive marmoset recovery model for in vivo efficacy assessment of CGRP receptor antagonists was developed in our laboratories, which utilizes laser Doppler facial blood flow as a surrogate for intracranial artery diameter. Briefly, marmosets were anesthetized and facial blood flow was increased by four intravenous (IV) administrations of hαCGRP (10 μg/kg) delivered at 45 min intervals (−30, 15, 60, and 105 min). The effect of antagonist, delivered subcutaneously (SC) at 0 min, on the hαCGRP-induced changes in facial blood flow was measured by laser Doppler flowmetry. In this model, compound 8 (Rimegepant hemisulfate, also known as BMS-927711) inhibited hαCGRP-induced increases in marmoset facial blood flow upon subcutaneous (SC) dosing. Compared to predose hCGRP control (−30 min), strong (>50%) inhibition of CGRP-induced effects on facial blood flow were observed with compound 8 dosed sc at 7 mg/kg at 15, 60, and 105 min postdose (Figure 2). Comparing activity versus exposure 15 min postdose, plasma levels of approximately 400 nM were associated with strong in vivo efficacy (>65% inhibition). In comparison, plasma levels of 5 above 1000 nM were needed for similar efficacy in this model. Peak inhibition for 8 was very strong at 75–80% at 60 and 105 min postdose, with corresponding plasma levels just below 800 nM (Figure 3).

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In vivo PK [1]
Compound 8 exhibited good oral bioavailability in the rat (FPO = 45%) and cynomolgus monkey (FPO = 67% as a solution). When dosed as a free base suspension of crystalline material, the oral bioavailability of 8 in the monkey remained good at 48%.

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In a novel non-invasive marmoset recovery model assessing CGRP receptor antagonist efficacy, subcutaneous (SC) administration of BMS-927711 (7 mg/kg) strongly inhibited human αCGRP (hαCGRP)-induced increases in facial blood flow. Compared to pre-dose CGRP control, strong (>50%) inhibition was observed at 15, 60, and 105 minutes post-dose. Peak inhibition was 75-80% at 60 and 105 minutes post-dose. Plasma levels of approximately 400 nM were associated with strong in vivo efficacy (>65% inhibition) at 15 minutes post-dose.[1]

Competition for [125I]CGRP Binding Assay: [1]
The ability of 8 to inhibit the binding of radiolabeled human alpha CGRP ([125I]CGRP) to human CGRP receptors was measured using a radioligand competition assay. Human neuroblastoma SK-N-MC cells, endogenously expressing the CGRP receptor, were used as the CGRP receptor source (Aiyar et al., 2001). 8 was first solubilized and serially diluted in 100% DMSO. Compound was further diluted 25 fold into assay buffer (50 mM Tris-Cl pH 7.5, 5 mM MgCl2, 0.005% Triton X-100) and transferred (50 µl) into 96 well assay plates. [125I]CGRP was diluted to 72 pM in assay buffer and 50 µl was added to each well (final concentration 18 pM in assay – Kd=27.7 pM). SK-N-MC membrane pellets were thawed, diluted in assay buffer with fresh 0.1% mammalian protease inhibitor cocktail, and homogenized. Homogenate (5 to 10 µg protein) was then added in a volume of 100 µl to each well. The assay plates were incubated at room temperature (25 °C) for two hours. Assays were terminated by the addition of excess cold wash buffer (50 mM Tris-Cl pH 7.5, 0.1% BSA) immediately followed by filtration over glass fiber filters pre-soaked in 0.5% PEI. Non-specific binding was defined as binding in the presence of 1 µM β-CGRP. Protein bound radioactivity was measured using a gamma scintillation counter. The IC50 was defined as the concentration of compound required to inhibit 50% of radioligand binding.

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CGRP receptor binding in other species [1]
S6 8 was tested for its potency at the CGRP receptor for marmoset (common marmosets (Callithrix jacchus)). Radioligand binding assays were used to assess the activity: 50 µg of brain homogenates from each species were used as the receptor source and 15 pM [125I]CGRP as the radioligand.

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CYP Inhibition Using Human Recombinant Enzymes[1]
The capacity of the test compounds to inhibit cDNA-derived CYP enzymes in microsomes prepared from baculovirus-infected insect cells was measured using either 3-cyano-7-ethoxycoumarin (CYP1A2 and CYP2C19), 7-methoxy-4-trifluoromethylcoumarin (CYP2C9) or 3-[2-(N,N-diethyl-Nmethylamino)ethyl]-7-methoxy-4-methylcoumarin (CYP2D6) as model substrates. CYP3A4 was tested with two substrates, 7-benzyloxy-4-trifluoromethylcoumarin (BFC) and benzoylresorufin. The 50% inhibitory concentration (IC50) for the test compound was determined for each enzyme. A single concentration of each model substrate, at approximately the apparent Km with the exception of BFC which was tested below the apparent Km, was incubated with 10 concentrations of the compound of interest ranging from 2 nM to 40 µM in 0.2% v/v DMSO. Metabolism of the model substrate was assayed by the production of 7-hydroxy-3-cyanocoumarin, 3-[2-(N,N-diethylamino)ethyl]-7-hydroxy-4- methylcoumarin, 7-hydroxy-4-trifluoromethylcoumarin or resorufin metabolites, and measured via fluorescence detection. Assays were conducted in 384-well microplates in a total volume of 30 µl. Incubations were performed for 45 min (20 min for the CYP3A4 BFC assay) with microsomes prepared from baculovirus-infected insect cells containing cDNAderived CYP enzymes, and utilized an NADPH generating system.

SK-N-MC CGRP Cellular/Functional Assay [1]
The CGRP receptor complex is coupled to the Gαs class of G protein. Binding of CGRP to this complex leads to the production of cyclic AMP (adenosine 3'5'-cyclic monophosphate) via Gαs-dependent activation of adenylate cyclase. 8 was evaluated as an inhibitor of human CGRP receptor signaling by measuring the compounds ability to inhibit CGRP-stimulated cyclic AMP formation in attached SK-N- S5 MC cells. SK-N-MC cells were preincubated with various concentrations of 8 or vehicle for 15 minutes. Agonist (300 pM αCGRP, EC50 = 26.7 + 2.7 pM n=3) was added and the samples were incubated at room temperature for 30 minutes. The cells were lysed and evaluated using an HTRF based cAMP detection kit. IC50 values were defined as the concentration of compound required to inhibit 50% of the 300 pM CGRP-stimulated cAMP production.

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Permeability and P-glycoprotein Interaction [1]
Permeability of 8 was assessed by the non-cell-based parallel artificial membrane permeability assay (PAMPA), as well as the cell-based Caco-2 cell model. The PAMPA permeability study was conducted with 100 µM 8 at room temperature for 4 hours at pH 5.5 and 7.4 using pION© lipid solution. The studies were performed in triplicate (i.e., 3 wells per compound) with mean values reported in nm/second. Caco-2 cell studies were performed with the monolayers cultured for approximately 21 days. Bi-directional permeability studies for 8 were conducted at concentrations of 3.7 to 100 µM, pH 7.4. A follow-up bi-directional study was also performed for 8 (3 µM, pH 7.4) in presence of a P-gp inhibitor (ketoconazole 20 µM and cyclosporin 20 µM on both sides). The inhibition of the transport of [ 3H]-digoxin (initial concentration 5 µM), a P-gp substrate, across the Caco-2 cell membrane by 8 (initial concentration 10 µM) was studied to evaluate the potential inhibitory effect of the compound on P-gp.

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The binding affinity for the human CGRP receptor was determined by measuring the inhibition of ¹²⁵I-CGRP binding to membranes prepared from SK-N-MC cells, which endogenously express the receptor.[1]
Functional receptor antagonism was determined by measuring the inhibition of CGRP-stimulated cAMP production in SK-N-MC cells.[1]

In Vivo Efficacy of 8 [Rimegepant hemisulfate (BMS927711 hemisulfate)] in Marmoset Facial Blood Flow[1]
To assess in vivo efficacy and duration of action, a control increase in facial blood flow is induced by administration of hαCGRP (10 µg/kg, IV) 30 min prior (-0.5 hr) to drug delivery. The CGRP antagonist compound under study is administered at time zero (0 min) and three additional hαCGRP challenges are delivered at 45 min intervals for ~2 hr (data collected at 0.25, 1 and 1.75 hrs post-dose). Plasma samples are obtained just before each of the three post-dose hαCGRP administrations, to define the antagonist levels on board at the time of hαCGRP agonist challenge. Each antagonist is administered across a range of doses to define the no-effect, first significant effect and maximal peak effect dose. In the present study, 8 [Rimegepant hemisulfate (BMS927711 hemisulfate)] is dosed from 0.3 to 7 mg/kg, SC. The highest dose (7 mg/kg for 8 [Rimegepant hemisulfate (BMS927711 hemisulfate)]) represents the maximum dose deliverable within solubility limits and constrained by vehicle volumes that do not disrupt baseline facial blood flow. Following testing, animals are returned to the transport cage and placed on a temperature controlled surface that keeps the animals warm until fully awake and ambulatory. Animals may be tested again after a 14-21 day rest and washout period.

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In Vivo Methods – Pharmacokinetics in Rat and Cynomolgus Monkey [1]
In the rat and monkey studies described below, 8 [Rimegepant hemisulfate (BMS927711 hemisulfate)] was administered IV as a solution in a polyethylene glycol 400 (PEG-400)/ethanol (90:10, v/v). Rat Male Sprague-Dawley rats (250-350 g) were used in the PK studies of 8 [Rimegepant hemisulfate (BMS927711 hemisulfate)]. Blood samples (~0.3 mL) were collected from the jugular vein into K3EDTA-containing tubes and then centrifuged at 4°C (1500-2000 x g) to obtain plasma, which was stored at -20°C until analysis by LC/MS/MS. In an oral bioavailability study with 8 [Rimegepant hemisulfate (BMS927711 hemisulfate)], 2 groups of animals (N = 3 per group) received the compound as an intra-venous (IV) bolus (1 mg/kg) via a jugular vein cannula or as a solution by oral gavage (10 mg/kg to fasted rats). The oral solution contained 8 [Rimegepant hemisulfate (BMS927711 hemisulfate)] dissolved in PEG-400/water (90:10, v/v). Serial blood samples were obtained predose and at 0.03 and 0.17 (IV only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 S9 hours post dose. Plasma samples, obtained by centrifugation at 4°C (1500-2000 x g), were stored at -20°C until analysis.

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Cynomolgus Monkey [1]
The PK of 8 was evaluated in a crossover-design study in male cynomolgus monkeys. Following an overnight fast (oral only), 3 animals (5.4 to 6.3 kg) received 8 [Rimegepant hemisulfate (BMS927711 hemisulfate)] by IV infusion (1 mg/kg over 5 minutes) via a femoral vein and by oral gavage as either a solution (10 mg/kg dissolved in 79.8% PEG400; 20% N-methylpyrrolidone; 0.2% Tween 80) or suspension of crystalline free base (10 mg/kg suspended in 98.95% water;1% povidone K-30; 0.05% docusate sodium), with at least a 2- week washout between treatments. Serial blood samples (~0.3 mL) were collected from a femoral artery predose and at 0.083, 0.17 (IV only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 hours post dose, and centrifuged at 4°C (1500-2000 x g) to obtain plasma. Samples were stored at -20°C until analysis by LC/MS/MS.

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For the in vivo efficacy assessment in marmosets, a novel non-invasive recovery model was used. Marmosets were anesthetized. Facial blood flow was increased by four intravenous (IV) administrations of hαCGRP (10 µg/kg) delivered at 45-minute intervals (at -30, 15, 60, and 105 minutes relative to antagonist dosing). The test antagonist, BMS-927711, was administered subcutaneously (SC) at time 0 minutes. The effect of the antagonist on the hαCGRP-induced changes in facial blood flow was measured using laser Doppler flowmetry.[1]

Absorption, Distribution and Excretion
The absolute oral bioavailability of retemapam hemisulfate is approximately 64%. After oral administration of the fast-dissolving tablet, peak plasma concentration (Tmax) is reached at 1.5 hours. When taken with a high-fat meal, Tmax is delayed by 1 hour, Cmax decreases by 42-53%, and AUC decreases by 32-38%. The clinical significance of these pharmacokinetic differences is unclear. In healthy subjects, after oral administration of radiolabeled retemapam hemisulfate, 78% of the radioactive material was recovered in feces, and 24% in urine. The unchanged parent drug is the major component of each formulation, accounting for 42% and 51% of the recovered dose, respectively. At steady state, the volume of distribution is approximately 120 L. Metabolism/Metabolites Remepam hemisulfate is primarily metabolized by CYP3A4, with weaker metabolic activity by CYP2C9. The specific metabolites of retrimapan hemisulfate have not been identified, and no major metabolite was detected in plasma. Approximately 77% of the administered dose was excreted unchanged, suggesting that metabolism may be a secondary pathway for drug clearance.

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Biological half-life
The elimination half-life in healthy subjects was approximately 11 hours.

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BMS-927711 demonstrated good oral bioavailability in both rats (Fpo = 45%) and cynomolgus monkeys (Fpo = 67% when administered in solution). [1]
When administered as a free base suspension of the crystalline substance, the oral bioavailability in monkeys remained good at 48%. [1]
In the marmoset model, after subcutaneous injection of 7 mg/kg BMS-927711, the plasma concentration was approximately 400 nM at 15 minutes post-administration and slightly less than 800 nM at 60 and 105 minutes post-administration. [1]
Preliminary Phase I human pharmacokinetic results are in good agreement with preclinical human pharmacokinetic predictions, and the effective exposure level is expected at a dose of 75 mg. [1]

Hepatotoxicity
In a pre-registration controlled trial of retamipine hemisulfate in thousands of patients, only a small number (1% to 2%) experienced mild to moderate elevations in serum transaminases, with an overall incidence similar to the placebo group. No clinically apparent liver injury has been reported with retamipine in the controlled trial or subsequent routine use. In contrast, ticagliptin, an oral CGRP receptor antagonist initially developed for migraine treatment, was abandoned during development due to clinically apparent liver injury in multiple patients. These liver injuries were characterized by significantly elevated serum transaminase levels and symptoms such as fatigue, nausea, and abdominal discomfort appearing within 2 to 4 weeks of starting treatment, with symptoms rapidly resolving upon discontinuation of the drug. No similar events have been reported with retamipine hemisulfate. Probability Score: E (Unlikely to be the cause of clinically apparent acute liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Currently, there is no information on the clinical use of retamipine hemisulfate during lactation. However, the concentration in breast milk is very low and is not expected to have any adverse effects on breastfed infants. If a mother of an older infant needs to take retamipine hemisulfate, this is not a reason to stop breastfeeding, but until more data is available, alternative medications may be preferred when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
The plasma protein binding rate of retamipine hemisulfate is approximately 96%. The specific proteins bound to retamipine hemisulfate are not yet clear.

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In pre-nomination and pre-IND toxicology studies, BMS-927711 demonstrated favorable predictive toxicology characteristics, supporting its selection for clinical development. [1]
In preliminary Phase I human studies, no significant adverse reactions were observed at doses up to 600 mg. [1]

[1]. J Med Chem . 2012 Dec 13;55(23):10644-51.

Rimegepant hemisulfate is an oral CGRP receptor antagonist developed by Biohaven Pharmaceuticals. It was approved by the US FDA on February 27, 2020, for the treatment of acute migraines, and by the European Commission in April 2022 for the treatment and prevention of migraines. While several parenteral antagonists of CGRP and its receptors have been approved for migraine treatment (e.g., erenumab, fremanezumab, galcanezumab), Rimegepant hemisulfate and ubrogepant were the only two CGRP antagonists with oral bioavailability before the approval of atogepant in 2021. Currently, the standard treatment for migraines is the use of triptans (e.g., sumatriptan) for acute attacks; however, these drugs are contraindicated in patients with pre-existing cerebrovascular and cardiovascular diseases due to their vasoconstrictive effects. CGRP pathway antagonists have become an attractive target for migraine treatment because, unlike triptans, oral CGRP antagonists do not exhibit observed vasoconstrictive effects, making them safer for patients with contraindications to standard therapy. Rimegepant hemisulfate is a calcitonin gene-related peptide receptor antagonist. The mechanism of action of retmegapan hemisulfate is as a calcitonin gene-related peptide receptor antagonist. Rimegepant hemisulfate is a small molecule calcitonin gene-related peptide (CGRP) receptor inhibitor that blocks the action of CGRP. CGRP is a potent vasodilator believed to play a role in migraines. Rimegepant hemisulfate is approved for the treatment of acute migraine attacks. In clinical trials, retmegapan hemisulfate was generally well-tolerated, with only a very few transient elevations in serum transaminases during treatment, and no clinically manifested cases of liver injury reported. See also: Rimegepant hemisulfate (active ingredient).

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Drug Indications
Remigrape hemisulfate is indicated for the acute treatment of migraine with or without aura in adults. Remigrape hemisulfate is also indicated for the prevention of episodic migraine in adults.
Vydura is indicated for the acute treatment of migraine with or without aura in adults; and for the preventive treatment of episodic migraine in adults with at least 4 attacks per month.
Treatment of Migraine
Prevention of Migraine

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Mechanism of Action
The currently accepted pathophysiological theory of migraine holds that dysfunction of the central nervous system, particularly the trigeminal ganglion, is the root cause of the disease. Activation of the trigeminal ganglion triggers stimulation of trigeminal nerve afferent fibers that project to the spinal cord and synapse with various intracranial and extracranial pain-sensing structures (such as the dura mater). The pain signal is then further transmitted via secondary ascending neurons to the brainstem, hypothalamus, and thalamic nuclei, and from there to multiple cortical areas (such as the auditory cortex, visual cortex, and motor cortex). The trigeminal ganglion appears to amplify and perpetuate migraine pain by activating perivascular fibers and releasing molecules involved in pain production, such as calcitonin gene-related peptide (CGRP). The alpha subtype of CGRP, expressed in primary sensory neurons, is a potent vasodilator and is closely linked to the pathogenesis of migraines—CGRP levels rise sharply during a migraine attack, return to normal after treatment with triptans, and intravenous infusion of CGRP has been shown to induce migraine-like headaches in migraine sufferers. In addition to its vasodilatory properties, CGRP appears to be a pro-pain factor, modulating neuronal excitability to promote pain responses. Rimegepant hemisulfate is a calcitonin gene-related peptide receptor antagonist—it competitively binds to these receptors with calcitonin gene-related peptide (CGRP), thereby blocking the effects of CGRP and its ability to amplify and exacerbate migraines, ultimately terminating the headache.

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Pharmacodynamics
Rimegepant hemisulfate helps terminate migraines by inhibiting the activity of a pro-pain molecule associated with migraine pathophysiology.
It is intended as a treatment for migraines and therefore has a relatively rapid onset of action. Most efficacy trials assess efficacy at 2 hours. No dose adjustment is required for patients with mild, moderate or severe renal impairment and mild or moderate hepatic impairment. In clinical trials, plasma concentrations of retemapam hemisulfate were significantly elevated in patients with severe hepatic impairment (i.e., Child-Pugh C), and its use should be avoided in such patients. Hypersensitivity reactions have been reported in clinical studies, and patients should be informed of this possibility. If a hypersensitivity reaction occurs, retemapam hemisulfate should be discontinued immediately.

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BMS-927711 (also referred to as compound 8 in the literature) is a potent oral small molecule calcitonin gene-related peptide (CGRP) receptor antagonist originally used to treat acute migraines. [1]
It was designed based on the lead compound (BMS-846372) by introducing a primary amine group to improve water solubility while maintaining its potency and permeability. [1]
The presence of the primary amine group significantly improves water solubility (50 µg/mL) without affecting bilayer membrane permeability, thereby enhancing ADME properties. [1]
This compound exhibits very good metabolic stability, an acceptable CYP inhibition profile, and favorable animal pharmacokinetics. [1]
BMS-927711 entered a Phase II clinical trial for migraine in [date missing]. Publication date. [1]

C28H28F2N6O3

583.607

1642783-82-1

1642783-82-1; 1642783-82-1 (0.5 sulfate); 1374024-48-2 (0.5 sulfate 1.5 hydrate); 2377164-85-5 (0.5 sulfate 3 hydrate); 1289023-67-1Rimegepant (BMS927711)

Typically exists as solids at room temperature

KRNAOFGYEFKHPB-ANJVHQHFSA-N

InChI=1S/C28H28F2N6O3/c29-20-6-1-4-17(23(20)30)18-8-9-22(25-19(24(18)31)5-2-12-32-25)39-28(38)35-14-10-16(11-15-35)36-21-7-3-13-33-26(21)34-27(36)37/h1-7,12-13,16,18,22,24H,8-11,14-15,31H2,(H,33,34,37)/t18-,22+,24-/m0/s1

[(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl] 4-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

5%DMSO + Corn oil: 5.0mg/ml (9.35mM) (Please use freshly prepared in vivo formulations for optimal results.)