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BI 224436 Sale

(Synonyms: 暂无) 目录号 : GC35510

BI 224436是一种新型的HIV-1非催化性位点整合酶抑制剂,对HIV-1实验室菌株的EC50值小于15 nM。

BI 224436 Chemical Structure

Cas No.:1155419-89-8

规格 价格 库存 购买数量
2mg
¥2,100.00
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5mg
¥3,150.00
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10mg
¥4,500.00
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50mg
¥13,500.00
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100mg
¥18,900.00
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Kinase experiment:

BI 224436 is dissolved in acetonitrile-methanol (50:50, vol/vol) to achieve a concentration of 1.5 mM. Phosphate buffer (pH 7.4), cofactor, and test substance or isoform-selective inhibitors are added to 96-well plates and are prewarmed to 37°C for 10 min. Cofactor concentrations are 1.3 mM NADP, 3.3 mM glucose-6-phosphate, and 0.4 U/mL glucose-6-phosphate dehydrogenase. Reactions are initiated by the addition of prewarmed (37°C) enzyme and substrate. Reaction mixtures are incubated at 37°C and terminated by the addition of 0.038 ml of 40:40:20 (vol/vol) methanol–acetonitrile–0.5 M Tris buffer. Formation of the fluorescent metabolites is measured using a microplate spectrofluorometer at specific excitation and emission wavelengths. The IC50 is determined using the 96-well 32 procedure supplied with the SAS software[1].

Animal experiment:

Rats: For oral PK studies, BI 224436 is administered in a suspension of 0.5% (wt/vol) methyl cellulose (MC), 0.3% (vol/vol) Tween 80, and 1% (vol/vol) N-methyl-2-pyrrolidine (MP) in water. For i.v. dosing, BI 224436 is dissolved in 70% PEG 400–30% water (vol/vol). The appropriate amount of BI 224436 is dissolved in PEG 400 with sonication. The rats receive a single i.v. dose of 0.2 mg/kg of body weight (1 mL/kg) via the jugular vein as a bolus or received a single oral dose of 0.4 mg/kg (10 mL/kg) administered by gavage. Blood samples are obtained at 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 32 h after dosing for analysis[1].

References:

[1]. Fenwick C, et al. Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor. Antimicrob Agents Chemother. 2014 Jun;58(6):3233-44.

产品描述

BI 224436 is a novel HIV-1 noncatalytic site integrase inhibitor with EC50 values of less than 15 nM against different HIV-1 laboratory strains. EC50: 15 nM (HIV-1)[1]

BI 224436 has cellular cytotoxicity of more than 90 μM. BI 224436 has a low, 2.1-fold decrease in antiviral potency in the presence of 50% human serum. BI 224436 retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. BI 224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI 224436 has drug-like in vitro absorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition[1].

BI 224436 exhibits excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%; F, 82%), and dog (CL, 8%; F, 81%)[1].

[1]. Fenwick C, et al. Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor. Antimicrob Agents Chemother. 2014 Jun;58(6):3233-44.

Chemical Properties

Cas No. 1155419-89-8 SDF
别名 暂无
Canonical SMILES CC1=C([C@@H](C(O)=O)OC(C)(C)C)[C@@]([C@@]2=CC=C3C4=C2N=CC=C4CCO3)=C5C(C=CC=C5)=N1
分子式 C27H26N2O4 分子量 442.51
溶解度 DMSO: ≥ 50 mg/mL (112.99 mM) 储存条件 Store at -20°C,unstable in solution, ready to use.
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1 mg 5 mg 10 mg
1 mM 2.2598 mL 11.2992 mL 22.5984 mL
5 mM 0.452 mL 2.2598 mL 4.5197 mL
10 mM 0.226 mL 1.1299 mL 2.2598 mL
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Research Update

Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor

Antimicrob Agents Chemother 2014 Jun;58(6):3233-44.PMID:24663024DOI:10.1128/AAC.02719-13.

BI 224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3'-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC50s) of <15 nM against different HIV-1 laboratory strains and cellular cytotoxicity of >90 μM. BI 224436 also has a low, ∼2.1-fold decrease in antiviral potency in the presence of 50% human serum and, by virtue of a steep dose-response curve slope, exhibits serum-shifted EC95 values ranging between 22 and 75 nM. Passage of virus in the presence of inhibitor selected for either A128T, A128N, or L102F primary resistance substitutions, all mapping to a conserved allosteric pocket on the catalytic core of integrase. BI 224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI 224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI 224436 has drug-like in vitro absorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%; F, 82%), and dog (CL, 8%; F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials.

Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

ACS Med Chem Lett 2014 Jan 22;5(4):422-7.PMID:24900852DOI:10.1021/ml500002n.

An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.

Next-generation integrase inhibitors : where to after raltegravir?

Drugs 2013 Mar;73(3):213-28.PMID:23413196DOI:10.1007/s40265-013-0015-5.

The integrase enzyme facilitates the incorporation of HIV-1 proviral DNA into the host cell genome and catalyses a function vital to viral replication. Inhibitors of this enzyme represent the newest class of antiretroviral drugs in our armamentarium to treat HIV-1 infection. Raltegravir, an integrase strand transfer inhibitor, was the first drug of this class approved by the US FDA; it is a potent and well tolerated antiviral agent. However, it has the limitations of twice-daily dosing and a relatively modest genetic barrier to the development of resistance. These qualities have prompted the search for agents with once-daily dosing, a more robust barrier to resistance, and a resistance profile of limited overlap with that of raltegravir. We review a series of integrase inhibitors that are in clinical or advanced pre-clinical studies. Elvitegravir, recently approved by the FDA as part of the elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine fixed-dose combination pill has the benefit of being part of a one-pill, once-daily regimen, but suffers from extensive cross-resistance with raltegravir. Dolutegravir is the most advanced second-generation integrase inhibitor, and it boasts good tolerability, once-daily dosing with no need for a pharmacological enhancer, and relatively little cross-resistance with raltegravir. S/GSK1265744 has been developed into a long-acting parenteral agent that shows a high barrier to resistance in vitro and the potential for an infrequent dosing schedule. BI 224436 is in early clinical trials, but is unlikely to demonstrate cross-resistance with other integrase inhibitors. The inhibitors of the lens epithelium-derived growth factor (LEDGF)/p75 binding site of integrase (LEDGINs) are extremely early in development. Each of these contributes a new benefit to the class and will extend the treatment options for patients with HIV-1 infection.

Investigational HIV integrase inhibitors in phase I and phase II clinical trials

Expert Opin Investig Drugs 2017 Nov;26(11):1207-1213.PMID:28956664DOI:10.1080/13543784.2017.1378643.

To date, three HIV integrase strand transfer inhibitors (INSTIs), i.e. raltegravir, elvitegravir and dolutegravir, have been approved for clinical use. Recent research has focused on new integrase inhibitors including those targeting non-catalytic sites of HIV integrase. Areas covered: This paper reviews two investigational INSTIs in phase I and II clinical trials, bictegravir (BIC) and cabotegravir (CAB), as well as an investigational noncatalytic integrase inhibitor (NCINI) termed BI 224436. Expert opinion: Data from phase I and II clinical trials demonstrate that CAB has good efficacy and is well-tolerated. CAB is promising because it can be formulated both orally and as a long-acting (LA) injectable for treatment and prevention of HIV infection. Since LA-CAB formulation offers the possibility of favourable dosing, it may help individuals who struggle with adherence issues. BIC also represents a promising safe, effective and well-tolerated drug that can be administered as a single once-daily regimen in coformulation with emtricitabine and tenofovir alafenamide (FTC/TAF). Ongoing phase III trials should clarify optimal doses and reveal the potential clinical advantages of these new drugs and formulations over other current regimens. Exploration of novel HIV integrase inhibitors acting through mechanisms different from those of INSTIs is still needed.

A palladium-catalyzed intramolecular carbonylative annulation reaction for the synthesis of 4,5-fused tricyclic 2-quinolones

Chem Commun (Camb) 2016 Jun 8;52(49):7665-7.PMID:27225232DOI:10.1039/c6cc02600a.

A concise and efficient synthetic route to 4,5-fused tricyclic 2-quinolones through the palladium-catalyzed carbonylative annulation of alkyne-tethered N-substituted o-iodoanilines has been developed. This reaction proceeds smoothly under mild reaction conditions and exhibits exceptional tolerance to a variety of functional groups. It has been successfully applied to the efficient synthesis of BI 224436, an HIV integrase inhibitor.