Bedaquiline

• CAT Number: I004115
• CAS Number: 843663-66-1
• Molecular Formula: C32H31BrN2O2
• Molecular Weight: 555.5
• Purity: ≥95%
• Solubility: Soluble in DMSO.
• Storage: Store at -20°C
• IUPAC Name: (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-naphthalen-1-yl-1-phenylbutan-2-ol
• InChI: InChI=1S/C32H31BrN2O2/c1-35(2)19-18-32(36,28-15-9-13-22-10-7-8-14-26(22)28)30(23-11-5-4-6-12-23)27-21-24-20-25(33)16-17-29(24)34-31(27)37-3/h4-17,20-21,30,36H,18-19H2,1-3H3/t30-,32-/m1/s1
• InChIKey: QUIJNHUBAXPXFS-XLJNKUFUSA-N
• SMILES: CN(C)CCC(C1=CC=CC2=CC=CC=C21)(C(C3=CC=CC=C3)C4=C(N=C5C=CC(=CC5=C4)Br)OC)O

Bedaquiline (CAT: I004115), also known as TMC207 or AIM 100, is not only used for the treatment of drug-resistant tuberculosis but also exhibits potent inhibitory activity against the Ack1 (TNK2) kinase. It shows high selectivity for Ack1 with an IC50 value of 22 nM while displaying no inhibition of 25 other kinases including ABL1, BTK, Lck, and LYN. The inhibition of Ack1 by bedaquiline has shown promising effects in inhibiting pancreatic cancer progression. It can suppress the activation of Ack1 and subsequent phosphorylation of the androgen receptor (AR) at Tyr267. This leads to the inhibition of AR-mediated transcriptional activity and its binding to promoters of PSA, NKX3.1, and TMPRSS2 genes.

Overview of Clinical Research

Bedaquiline is an adenosine triphosphatase inhibitor. It is registered for Tuberculosis (In children, Combination therapy) in USA (PO).

Reference

1. Infect Drug Resist. 2015 Oct 30;8:367-78. doi: 10.2147/IDR.S68351. eCollection 2015.
New developments in the treatment of drug-resistant tuberculosis: clinical utility of bedaquiline and delamanid.
Brigden G(1), Hewison C(2), Varaine F(2).
Author information:
(1)Access Campaign, Médecins Sans Frontières, Geneva, Switzerland. (2)Medical Department, Médecins Sans Frontières, Paris, France.
The current treatment for drug-resistant tuberculosis (TB) is long, complex, and associated with severe and life-threatening side effects and poor outcomes. For the first time in nearly 50 years, there have been two new drugs registered for use in multidrug-resistant TB (MDR-TB). Bedaquiline, a diarylquinoline, and delamanid, a nitromidoxazole, have received conditional stringent regulatory approval and have World Health Organization interim policy guidance for their use. As countries improve and scale up their diagnostic services, increasing number of patients with MDR-TB and extensively drug-resistant TB are identified. These two new drugs offer a real opportunity to improve the outcomes of these patients. This article reviews the evidence for these two new drugs and discusses the clinical questions raised as they are used outside clinical trial settings. It also reviews the importance of the accompanying drugs used with these new drugs. It is important that barriers hindering the use of these two new drugs are addressed and that the existing clinical experience in using these drugs is shared, such that their routine-use programmatic conditions is scaled up, ensuring maximum benefit for patients and countries battling the MDR-TB crisis.
2. Pharmacotherapy. 2014 Nov;34(11):1187-97. doi: 10.1002/phar.1482. Epub 2014 Sep 9.
Bedaquiline: a novel antitubercular agent for the treatment of multidrug-resistant tuberculosis.
Worley MV(1), Estrada SJ.
Author information:
(1)Department of Pharmacy, Lee Memorial Health System, Fort Myers, Florida.
Bedaquiline is a diarylquinoline antitubercular drug with a novel mechanism of action against Mycobacterium tuberculosis. Bedaquiline works by inhibiting bacterial adenosine triphosphate (ATP) synthase and represents the first novel class of antituberculosis agents in more than 40 years. Bedaquiline is indicated for the treatment of multidrug-resistant tuberculosis (MDR TB) in combination with at least three other antitubercular drugs when no other effective regimen is available. The recommended bedaquiline dosage is 400 mg orally once/day for 2 weeks followed by 200 mg orally 3 times/week for 22 weeks. Bedaquiline should be administered with food, which increases the bioavailability 2-fold. Bedaquiline is metabolized by cytochrome P450 isoenzyme 3A4 and is impacted by both inducers and inhibitors of this isoenzyme. Concentration-dependent bactericidal activity was observed in laboratory and murine studies. Accelerated approval was granted in the United States and European Union based on the results of two phase IIb clinical studies that used sputum culture clearance as a surrogate end point for clinical efficacy. These studies showed greater sputum culture clearance up to week 24 for the bedaquiline group compared with placebo. Common adverse events in clinical trials included nausea, arthralgia, and headache. Serious adverse events included elevated serum transaminase levels and rate-corrected QT-interval prolongation. Unexplained higher mortality was seen in patients receiving bedaquiline versus those receiving placebo. Bedaquiline is a novel agent with a unique mechanism of action and has the potential to meet a great need in patients with MDR TB who have no other treatment options. Due to safety concerns and limited clinical information, phase III trials are needed to fully determine its place in therapy.
3. J Antimicrob Chemother. 2014 Sep;69(9):2310-8. doi: 10.1093/jac/dku171. Epub 2014 May 23.
Bedaquiline: a review of human pharmacokinetics and drug-drug interactions.
van Heeswijk RP(1), Dannemann B(2), Hoetelmans RM(3).
Author information:
(1)Janssen Infectious Diseases BVBA, Beerse, Belgium . (2)Janssen Research & Development, LLC, Titusville, NJ, USA. (3)Janssen Infectious Diseases BVBA, Beerse, Belgium.
Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (rifampicin, rifapentine, isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies.
4. Tuberculosis (Edinb). 2014 Jul;94(4):357-62. doi: 10.1016/j.tube.2014.04.001. Epub 2014 Apr 18.
Bedaquiline for the treatment of resistant tuberculosis: promises and pitfalls.
Kakkar AK(1), Dahiya N(2).
Author information:
(1)Dept. of Pharmacology, All India Institute of Medical Sciences, Bhopal 462024, India. Electronic address: . (2)Dept. of Preventive and Social Medicine, Lady Hardinge Medical College, New Delhi, India.
Treatment of multidrug-resistant tuberculosis (MDR-TB) is hindered by limited efficacy and significant toxicity of second-line drugs. The need for new therapeutic options is critical to combat the global MDR-TB epidemic. Bedaquiline is a novel oral diarylquinoline approved by Food and Drug administration (FDA) for the treatment of adults with pulmonary MDR-TB on the basis of Phase IIb trial data under the provisions of the accelerated approval regulations for serious or life-threatening conditions. The FDA advisory committee members voted unanimously on efficacy data based on surrogate measures, however they were split on the issues of safety of bedaquiline. Main safety concerns include QT interval prolongation, hepatic related adverse events, and excess mortality in bedaquiline treated patients. While bedaquiline approval is a story of many firsts and certainly a welcome addition to the existing arsenal of anti-TB agents, a cautiously optimistic approach is required to assess the risk benefit profile of the drug. Acceleration of further Phase III trials and clinical studies is imperative, as is timely analysis of emerging data on the real world use of the drug. This mini review outlines the clinical pharmacology of bedaquiline highlighting the potential promises and challenges that implicate the risk benefit profile of drug.