Brivanib (BMS-540215)

Brivanib is an ATP competitive inhibitor of human VEGFR-2 with IC50 value of 25nM [1].

Brivanib is a selective RTK inhibitor that targets signaling via VEGFR2 and 3, and FGFR1, 2 and 3. Targeting both VEGF and FGF signaling pathways inhibits tumor growth in RT2 mice, with VEGF signaling predominating in initiation of tumor angiogenesis, Currently, brivanib therapy is being evaluated in phase III clinical trials in colorectal carcinoma and hepatocellular carcinoma (HCC) and in phase II trials for numerous indications including brivanib second-line therapy following sorafenib failure [2].

Brivanib has moderate potency against VEGFR-1 and FGFR-1 and good selectivity against PDGFR-β. In the preclinical in vivo mouse models, it is also found to be a good inhibitor of Flk-1, the mouse homologue of VEGFR-2 with IC50 value of 89 nM. Brivanib is reported to inhibit the proliferation of human umbilical vein endothelial cells (HUVEC) with potency against VEGF-stimulated HUVECs and FGF-stimulated HUVECs. The IC50 values are 40 nM and 276nM respectively. When tested against human tumor cell lines, Brivanib shows lower antiproliferative potency. In particular, activity was low against the cell line used in the in vivo tumor xenograft mouse efficacy model (H3396) [1].

References:
[1] Rajeev S. Bhide, Zhen-Wei Cai, Yong-Zheng Zhang, Ligang Qian, Donna Wei, Stephanie Barbosa, Louis J. Lombardo, Robert M. Borzilleri, Xiaoping Zheng, Laurence I. Wu, Joel C. Barrish, Soong-Hoon Kim, Kenneth Leavitt, Arvind Mathur, Leslie Leith, Sam Chao, Barri Wautlet, Steven Mortillo, Robert Jeyaseelan Sr., Daniel Kukral, John T. Hunt, Amrita Kamath, Aberra Fura, Viral Vyas, Punit Marathe, Celia D’Arienzo, George Derbin, and Joseph Fargnoli. Discovery and Preclinical Studies of (R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an In Vivo Active Potent VEGFR-2 Inhibitor. Journal of Medicinal Chemistry. 2006, 49 (7): 2143-2146.
[2] Elizabeth Allen, Ian B. Walters, and Douglas Hanahan. Brivanib, a Dual FGF/VEGF Inhibitor, Is Active Both First and Second Line against Mouse Pancreatic Neuroendocrine Tumors Developing Adaptive/Evasive Resistance to VEGF Inhibition. Clinical Cancer Research. 2011 (17): 5299-5310.

Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4] triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215).[Pubmed:18288793]

J Med Chem. 2008 Mar 27;51(6):1976-80.

A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.

Preclinical pharmacokinetics and in vitro metabolism of brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug brivanib alaninate.[Pubmed:19396600]

Cancer Chemother Pharmacol. 2009 Dec;65(1):55-66.

PURPOSE: Brivanib alaninate is a prodrug of Brivanib (BMS-540215), a potent oral VEGFR-2 inhibitor and is currently in development for the treatment of hepatocellular and colon carcinomas. In vitro and in vivo studies were conducted to characterize the preclinical pharmacokinetics and disposition of brivanib and brivanib alaninate, and antitumor efficacy in mice bearing human xenografts. METHODS: In vitro studies were conducted in liver and intestinal fractions, plasma and Caco-2 cells to assess the metabolic stability. Pharmacokinetics of brivanib were determined in preclinical species after administration of single intravenous or oral doses of both brivanib and brivanib alaninate. The antitumor efficacy was assessed at equimolar doses in nude mice bearing human tumor xenografts. Human efficacious dose was predicted based on projected human pharmacokinetic parameters and exposure at efficacious doses in the mouse efficacy models. RESULTS: In vitro and in vivo studies indicated that brivanib alaninate was efficiently converted to brivanib. Brivanib showed good brain penetration in rats consistent with its high intrinsic permeability and lack of active efflux in Caco-2 cells. The oral bioavailability of brivanib varied among species (22-88%) and showed dissolution rate-limited absorption even when combined with organic co-solvents. Administration of brivanib as brivanib alaninate allowed completely aqueous vehicles, and an improvement in the oral bioavailability (55-97%) was observed. The clearance of brivanib in humans is anticipated to be low to intermediate (hepatic extraction ratio < 0.7), while its volume of distribution is expected to be high. The minimum efficacious dose of brivanib alaninate was determined to be 60 mg/kg per day. CONCLUSIONS: Brivanib alaninate is rapidly and efficiently converted to the parent, brivanib, as demonstrated both in vitro and in vivo and offers an excellent mode to deliver brivanib orally.

Brivanib is an ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM, and has moderate potency against VEGFR-1 and FGFR-1, but >240-fold against PDGFR-β.

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