FDA Approves Boron(B) Drug Overview

The textL-Daycan play an important role in drug design given that boron and carbon and nitrogen (the two required atoms that make up the main chain of life) are located in the same cycle, and that boron atomic centers are prone to chemical properties such as the neutral triangular plane sp2 hybridization into tetrahedron sp3 hybridizationSince the late 1990s, small molecules based on boron have been increasingly present in the literature, whether in chemical synthesis, biological research or pharmaceutical researchSince 2003, the FDA has approved the marketing of five boron-containing drugsThe following will be detailedBortezomib was originally synthesized in Myogenics in 1995The drug then conducted a small Phase I clinical trial for patients with multiple myelomaFurther clinical trials were conducted by Millennium Pharmaceuticals in October 1999Fda approval for multiple myeloma treatment in May 2003In normal cells, proteases are involved in the degradation of ubiquitin proteinsHowever, in cancer cells, proteases degrade the apoptosis proteins in cancer cells, such as p53Boron atoms in boronitis inhibit the activity of proteases by specific catalyzing the active sites of 26S proteases, so that the apoptotic proteins in cancer cells are not degraded, which in turn leads to cell cycle stagnation and apoptosisafter subcutaneous administration, the plasma peak level is 25-50nM and lasts for 1-2 hoursAfter intravenous injection, the plasma peak level is about 500nM, but lasts only about 5 minutes, after which the concentration of the drug distributed to the tissue decreases rapidly (distribution volume is about 500L)In addition, boronzomi is metabolized mainly by cytochrome P450 enzymes 3A4, 2C19 and 1A2 oxidation, but not through CYP2D6 and 2C9 enzymes Patients with advanced malignancies had an average elimination half-life of 9 to 15h after taking doses of 1.45 to 2.00mg/m2 bobotimi and were removed through liver metabolism this drug is approved based on the results of international, randomized, double-blind Phase II and Phase III clinical trials Two Open Phase II clinical trials (SUMMIT and CREST) determined the efficacy of botozolmi 1.3mg/m2 in the 1, 4, 8 and 11 days of the 21-day cycle, and effectively extended the life cycle of patients with recurrent/difficult multiple myeloma with severe pretreatment Phase III APEX trial sat out that boronitomi 1.3mg/m2 was superior to the high-dose dexamethasone programme (e.g median TTP6.2 vs3.5 months, 1 year survival rate of 80% vs66%) Ixazomib, a second-generation protease inhibitor developed by Takeda Corporation of Japan, was approved by the FDA in November 2015 as the first oral drug for multiple myeloma treatment and in combination with two other therapies (Tonala and dexamethasone) for patients who have received at least one previous treatment In controlling myeloma growth and preventing bone loss, it has the same effect as boronzomi Ixazomib is a dipeptide-based leucine boric acid that counter-inhibits the CT-L protein hydrolysis (beta 5) site of 20S proteases Higher concentrations of Ixazomib also inhibit the protein hydrolytic beta 1 and beta 2 subprimes and induce the accumulation of ubiquitin proteins After oral administration , the time to reach the maximum concentration of plasma was 1h, and the average absolute bioavailability was 58% Ixazomib is metabolized mainly through CYP and non-CYP pathways, while CYP isoenzymes are not involved in its metabolism Ixazomib was meted at a higher clinical concentration than a variety of CYP subtypes metabolizing 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (1%) In addition, the drug was mainly removed by the kidneys and had a terminal half-life of 9.5 days, The trial included 722 patients with multiple myeloma recurrence The subjects were treated with ishadoni plus dexamethasone and placebo plus nalone amine and dexamethasone, respectively The trial achieved better efficacy and safety, significantly prolonging the patient's progressionless survival (Progression FreeSurvival, PFS) Patients who took isazolami had a longer disease-free deterioration period, at 14.7 months and 20.6 months, respectively, compared to patients who took a placebo, and had significantly lower rates of adverse events compared to boronzomi Tavaborole, Anacor's first boron-based local antifungal drug, was approved by the FDA on July 7, 2014, for local treatment of toenail fungal infections Anacor focuses on the development and production of boron-based drugs, and according to its latest news, Tavaborole could also be used for nail infections in the future Tavaborole performs its antifungal activity by forming a compound by metabolites to block cell protein synthesis by transferring RNA (tRNA) synths to cytoplasm After single administration, Tavaborole's average peak concentration (Cmax) was 3.54 to 2.26 ng/mL and the average AUClast was 44.4 to 25.5 nghr/mL Daily administration, after 2 weeks, the average Cmax is 5.17 to 3.47 ng/mL, and the average AUC is 75.8 to 44.5 nghr/mL In addition, Tavaborole showed antifungal effects 5 days after local administration, with a half-life of 28.5h, and metabolized mainly through the kidneys to remove metabolites produced by sulfate bindings and benzoic acid metabolites The FDA determined the effectiveness and safety of Tavaborole based on two multicenter, randomized, double-blind clinical trials that included 1,194 patients Clinical trials compared Tavaborole to local excipients containing active skin care ingredients The main endpoint is "complete cure", defined as a completely clean toenail (0% clinical lesions), while KOH tests and cultures negative determine the cure of fungal infections In both trials, the proportion of complete cure was 6.5% and 9.1%, respectively, and the proportion of total cure was 0.5% and 1.5% in the control group using excipients The secondary endpoint is "complete or near full cure", i.e the cure of fungal infection at the same time clinical lesions are less than 10%, or only the cure of fungal infection Tavaborole showed a clear advantage in both cases Tavaborole is usually well tolerated and most adverse events are reported to be mild and unrelated to treatment More than 1% of the participants had treatment-related adverse events including peeling at the application site, erythema at the application site and dermatitis at the application site, and inward growth of toenails Crisaborole was approved by the FDA on December 14, 2016 as a local treatment for mild to moderate asexual dermatitis Its structure consists of a boron atom that helps the skin penetrate and binds to the bimetallic center of phosphocythane 4 (PDE4) In addition, the drug is currently being developed as a local treatment for psoriasis Crisaborole's inhibition of phosphocyaphosphate 4 (PDE4) led to elevated cyclic monophosphate adenosine (cAMP) levels Increased levels of cAMP in cells inhibit the NF-kB pathway and inhibit the release of pro-inflammatory media such as TNF-alpha and various interleukins, thus treating acursions and psoriasis Crisaborole has a binding rate of 97% to human plasma proteins and is metabolized to 5-(4-cyanide oxyoxanous) -2-hydroxyxycarine (metabolites 1) and 5-(4-cyanoxyl)-2-hydroxylbenzoic acid (metabolite 2) Kidney discharge metabolites are crisabolo's primary removal pathway the drug was approved based on the results of a clinical trial (AD-303) in a multicenter, open 48-week long-term safety study During key studies and AD-303, 65% of patients reported a level 1 adverse event (TEAE), the majority of which were mild (51.2%) or moderate (44.6%), and those not related to treatment (93.1%) The frequency and severity of TEAE occurrence is consistent The most common adverse treatment-related adverse reactions (10.2% overall) were allergic dermatitis (3.1%), app-site pain (2.3%) and application site infection (1.2%) Nine patients (1.7%) stopped long-term studies of the drug because of TEAE The results of the trial showed that the associated adverse events were very low in patients treated with atopic dermatitis for 48 weeks using Crisaborole ointment Vabomere is a beta-lactamase inhibitor based on the ring boric acid drug cell and is made up of Vaborbactam and Meropenem It has been used in treatment trials for bacterial infection in patients with varying degrees of renal insufficiency In August 2017, the FDA approved Vabomere for the treatment of adult patients with complex urinary tract infections (cUTI) Vabomere is a cyclic boric acid drug-effect beta-lactamase inhibitor that effectively inhibits klebintoase in pneumonia (KPC) and other Ambler A (CTX-M, SHV, TEM) and C (P99, MIR, FOX) enzymes (e.g serine beta-lactamase) There was no inhibition effect on Class D or Class B carbon penicillin enzyme In addition, when used in combination with meropinan, Vabomere acts as a non-suicidal beta-lactamase inhibitor that protects meropinan from the degradation of serine beta-lactamase (e.g Klebseinase pneumoniae, KPC) In healthy adult subjects, Cmax after multiple infusions of 2g of Vabomere was 55.6 mg/L, AUC was 588mg/h/L, and half-life was 1.68h Under the same administration, Cmax in stable condition was 71.3 mg/L and AUC was 835mg/h/L After repeated administration, Vabomere's Cmax and AUC exposures do not change and do not accumulate in the plasma The average serum protein binding rate of Vabomere is about 33% In addition, the drug is mainly removed by the kidneys, of which about 75 to 95 per cent of the dose is excreted from urine within 24 to 48h this approval is based on the results of an international, randomized, double-blind Phase III clinical trial The trial recruited 545 people, with an average age of 52.8 years, 66.2% of women and 93.2% of patients completed the study The study found that 98.4 percent of patients in the Meropinan-Vaborbactam treatment group reached the main endpoint and 94.0 percent of patients in the merophein-Vaborbactam treatment group reached the primary endpoint In the treatment of the intended population, the rate of disease-causing microbial eradication was 66.7 per cent vs 57.7 per cent vs Tazobatan, a difference of 9 per cent, and in the population of pathogenic microorganismassessment, the rate of pathogenic microbial eradication in the population, and the rate of disease-causing microbial eradication in the patient population, and the rate of disease-causing microbial eradication, merropain-Vaborbacvs pyrasilin-tatzobatan, was 66.3 per cent vs60.4 per cent, with a difference of 5.9 per cent Adverse event rate, Meropinan-Vaborbactamvs Eracelin-Tazobatan is 39.0% vs35.5% in drug discovery, the trend of combining boron into drug chemistry research has been steadily increasing in recent years So far, the FDA has approved five boron-containing drugs, and several others are in clinical trials Boron-containing drugs have a variety of desired properties that lead to increased use, including potentially enhancing the effectiveness of drugs and improving their pharmacokinetic properties The discovery of boron-containing drugs promises to clarify the advantages of boron doping and encourage medical and pharmaceutical chemists to see boron-containing compounds as possibilities and solutions in their drug discovery programs