Biaryl Urea Research Articles

Exploration of pyridine containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors

The diacylglycerol acyltransferase enzyme, DGAT1, presents itself as a potential target for obesity as this enzyme is dedicated to the final committed step in triglyceride biosynthesis. Biphenyl ureas, exemplified by compound 4, have been reported to be potent hDGAT1 inhibitors. We have synthesized and evaluated 2-pyridyl and 3-pyridyl containing biaryl ureas as hDGAT1 inhibitors. Our aim was to incorporate a heteroaryl scaffold within these molecules thereby improving the cLogP profile and making these compounds more drug-like. Compounds within this series exhibited potent hDGAT1 inhibition when evaluated using an in vitro enzymatic assay. Selected compounds were also subjected to an oral fat tolerance test in mice where the percent triglyceride reduction versus a vehicle control was evaluated. Of the studied heteroaryl analogs compound 44 exhibited an in vitro IC(50) of 17nM and a plasma triglyceride reduction of 79% along with a 12-fold improvement in solubility over the biphenyl urea compound 4.

2-Aminobenzimidazoles as potent Aurora kinase inhibitors

This Letter describes the discovery and key structure–activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 ( 1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

UNEXPECTED STIMULATION OF MIGRATION AND PROLIFERATION OF DIFFERENT HUMAN UROTHELIAL CANCER CELL LINES BY SORAFENIB VIA ACTIVATION OF THE ERK-1/2 SIGNALING PATHWAY

You have accessJournal of Urology1 Apr 2009UNEXPECTED STIMULATION OF MIGRATION AND PROLIFERATION OF DIFFERENT HUMAN UROTHELIAL CANCER CELL LINES BY SORAFENIB VIA ACTIVATION OF THE ERK-1/2 SIGNALING PATHWAY Achim Rose, Roberto Rossi, Frank vom Dorp, Maria Grandoch, Christoph Börgermann, Artur A. Weber, and Herbert Rübben Achim RoseAchim Rose More articles by this author , Roberto RossiRoberto Rossi More articles by this author , Frank vom DorpFrank vom Dorp More articles by this author , Maria GrandochMaria Grandoch More articles by this author , Christoph BörgermannChristoph Börgermann More articles by this author , Artur A. WeberArtur A. Weber More articles by this author , and Herbert RübbenHerbert Rübben More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(09)61164-2AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "UNEXPECTED STIMULATION OF MIGRATION AND PROLIFERATION OF DIFFERENT HUMAN UROTHELIAL CANCER CELL LINES BY SORAFENIB VIA ACTIVATION OF THE ERK-1/2 SIGNALING PATHWAY." The Journal of Urology, 181(4S), p. 410 © 2009 by American Urological AssociationFiguresReferencesRelatedDetails Volume 181Issue 4SApril 2009Page: 410 Advertisement Copyright & Permissions© 2009 by American Urological AssociationMetricsAuthor Information Achim Rose More articles by this author Roberto Rossi More articles by this author Frank vom Dorp More articles by this author Maria Grandoch More articles by this author Christoph Börgermann More articles by this author Artur A. Weber More articles by this author Herbert Rübben More articles by this author Expand All Advertisement PDF downloadLoading ...

Sorafenib

Sorafenib (Nexavar) is an orally active multikinase inhibitor that is approved in the EU for the treatment of hepatocellular carcinoma. Monotherapy with sorafenib prolongs overall survival and delays the time to progression in patients with advanced hepatocellular carcinoma who are not candidates for potentially curative treatment or transarterial chemoembolization. Sorafenib is generally well tolerated in patients with advanced hepatocellular carcinoma. Thus, sorafenib represents an important advance in the treatment of advanced hepatocellular carcinoma and is the new standard of care for this condition. The bi-aryl urea sorafenib is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors (e.g. vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta) and downstream intracellular serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in tumour cell proliferation and tumour angiogenesis. In vitro, dose-dependent inhibition of cell proliferation and induction of apoptosis was seen with sorafenib in human hepatocellular carcinoma cells lines. Sorafenib demonstrated dose-dependent antitumour activity in a murine xenograft model of human hepatocellular carcinoma. Steady-state plasma concentrations were reached within 7 days in patients with advanced, refractory solid tumours who received twice-daily oral sorafenib. Metabolism of sorafenib occurs primarily in the liver and is mediated via cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase 1A9. In advanced hepatocellular carcinoma, differences in sorafenib pharmacokinetics between Child-Pugh A and B patients were not considered clinically significant. Sorafenib may be associated with drug interactions. For example, sorafenib exposure was reduced by an average 37% with concomitant administration of the CYP3A4 inducer rifampicin (rifampin); sorafenib concentrations may also be decreased by other CYP3A4 inducers. Monotherapy with oral sorafenib 400 mg twice daily prolonged median overall survival and delayed the median time to progression in patients with advanced hepatocellular carcinoma, according to the results of two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial and the Asia-Pacific trial). There was no significant difference between sorafenib and placebo recipients in the median time to symptomatic progression in either trial. The vast majority of patients included in these trials were Child-Pugh A. Combination therapy with sorafenib plus doxorubicin did not delay the median time to progression to a significant extent compared with doxorubicin alone in patients with advanced hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II trial. However, the median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone. Combination therapy with sorafenib plus tegafur/uracil or mitomycin also showed potential in advanced hepatocellular carcinoma, according to the results of noncomparative trials. Monotherapy with oral sorafenib was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse effect profile; diarrhoea and hand-foot skin reaction were consistently the most commonly occurring drug-related adverse events in clinical trials. In the SHARP trial, drug-related adverse events of any grade occurring in significantly more sorafenib than placebo recipients included diarrhoea, hand-foot skin reaction, anorexia, alopecia, weight loss, dry skin, abdominal pain, voice changes and 'other' dermatological events. A similar tolerability profile was seen in the Asia-Pacific trial. As expected given the addition of a chemotherapy agent, the adverse event profile in patients with advanced hepatocellular carcinoma who received combination therapy with sorafenib plus doxorubicin differed somewhat to that seen with sorafenib monotherapy in the SHARP trial. In patients receiving sorafenib plus doxorubicin, the most commonly occurring all-cause adverse events (all grades) included fatigue, neutropenia, diarrhoea, elevated bilirubin levels, abdominal pain, hand-foot skin reaction, left ventricular dysfunction, hypertension and febrile neutropenia.

Sorafenib in Hepatocellular Carcinoma: Separating the Hype From the Hope

Sorafenib in Hepatocellular Carcinoma: Separating the Hype From the Hope

Identification and characterization of pseudoirreversible nonpeptide antagonists of the neuropeptide Y Y 5 receptor and development of a novel Y 5-selective radioligand

The neuropeptide Y (NPY) Y 5 receptor is believed to be involved in the central regulation of appetite. Thus, antagonists of this receptor have been pursued as potential therapeutic agents for the treatment of obesity. A novel series of potent and selective phenylamide or biaryl urea NPY Y 5 receptor antagonists was identified. Four representative compounds from this series, SCH 208639 (N-[4-[(1,1-dimethylbutyl)thio]phenyl]-2,2-dimethylpropanamide), SCH 430765 (N-[[[3′-fluoro[1,1′-biphenyl]-4-yl]amino]carbonyl]-N-methyl-1-(methylsulfonyl)-4-piperidinamine), SCH 488106 (N-[[[3′,5′-difluoro[1,1′-biphenyl]-4-yl]amino]carbonyl]-N-methyl-1-[(5-methyl-3-pyridinyl)carbonyl]-4-piperidinamine) and SCH 500946 (N-[[[5-(3,5-difluorophenyl)-2-pyrazinyl]amino]carbonyl]-N-methyl-1-(methylsulfonyl)-4-piperidinamine), behaved as competitive antagonists in radioligand binding assays, but displayed apparently insurmountable antagonism in a cell-based functional assay. The apparently insurmountable antagonism was due to slow receptor dissociation rates rather than covalent binding, because the antagonists' effects could be reduced by extensive washing of cells after antagonist exposure. A novel radioligand, [ 35S]SCH 500946, was also developed and used to characterize the interaction of these antagonists with the NPY Y 5 receptor. [ 35S]SCH 500946 had high affinity for the NPY Y 5 receptor ( K d = 0.29 nM), and the binding kinetics ( k on 4.414 × 10 7 M − 1 min − 1 ; k off 0.009816 min − 1 ) confirmed that the compound slowly dissociates from the receptor. In a competition binding assay, NPY failed to displace [ 35S]SCH 500946 completely, indicating that the binding sites for NPY and [ 35S]SCH 500946 are not identical. These data indicate that the apparent insurmountable antagonism of these NPY Y 5 receptor antagonists is attributable both to slow receptor dissociation rates and to binding at a site distinct from NPY.

Design and synthesis of orally efficacious benzimidazoles as melanin-concentrating hormone receptor 1 antagonists

Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthesized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent obesity model.

BAY 43-9006 Inhibition of Oncogenic RET Mutants

Medullary and papillary thyroid carcinomas are often associated with oncogenic activation of the RET tyrosine kinase. We evaluated whether the biaryl urea BAY 43-9006, which is known to inhibit several other tyrosine kinases, blocks RET kinase function and oncogenic activity. We examined BAY 43-9006 activity against oncogenic RET in vitro and in cellular RET signaling in oncogenic RET-transfected NIH3T3 fibroblasts by using immunocomplex kinase assays and immunoblotting with phospho-specific antibodies. The effects of BAY 43-9006 on proliferation of human TPC1 and TT thyroid carcinoma cells, which harbor spontaneous oncogenic RET alleles, and on RAT1 fibroblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and flow cytometry. Growth of TT cell-derived xenograft tumors in athymic mice treated orally with BAY 43-9006 or with vehicle was measured. All statistical tests were two-sided. BAY 43-9006 inhibited oncogenic RET kinase activity at half-maximal inhibitory concentrations (IC50s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fibroblasts transformed by oncogenic RET and of thyroid carcinoma cells that harbor spontaneous oncogenic RET alleles. Moreover, BAY 43-9006 inhibited the growth of cells carrying RET V804L (IC50 = 110 nM, 95% confidence interval [CI] = 88 to 133 nM) or RET V804M (IC50 = 147 nM, 95% CI = 123 nM to 170 nM), both mutants that are resistant to anilinoquinazolines and pyrazolopyrimidines. After 3 weeks of oral treatment with BAY 43-9006 (60 mg/kg/day), the volume of TT cell xenografts (n = 7) was reduced from 72.5 to 44 mm3 (difference = 28.5 mm3, 95% CI = 7 mm3 to 50 mm3), whereas in vehicle-treated mice (n = 7), mean tumor volume increased to 408 mm3 (difference = 320 mm3, 95% CI = 180 mm3 to 460 mm3; untreated versus treated, P =.02). This inhibition paralleled a decrease in RET phosphorylation. BAY 43-9006 is a powerful inhibitor of the RET kinase. Its potential as a therapeutic tool for RET-positive thyroid tumors, including those expressing V804 mutations merits study.

Angiogenesis Inhibitors and Hypertension: An Emerging Issue

Angiogenesis Inhibitors and Hypertension: An Emerging Issue

Biaryl diamides as potent melanin concentrating hormone receptor 1 antagonists

Herein, we report the discovery of the potent and selective biaryl diamide derived MCH-R1 receptor antagonist 1, which was identified upon modification of a previously disclosed biaryl urea series. This paper describes one of the strategies incorporated to remove the highly mutagenic biarylaniline present in an otherwise promising biaryl urea series.

794 ORAL Randomized Phase III trial of the multi-kinase inhibitor sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma (RCC)

Activating mutations in Ras and B‐RAF were identified in several human cancers. In addition, several receptor tyrosine kinases, acting upstream of Ras, were found either mutated or overexpressed in human tumors. Because oncogenic activation of the Ras/RAF pathway may lead to a sustained proliferative signal resulting in tumor growth and progression, inhibition of this pathway represents an attractive approach for cancer drug discovery. A novel class of biaryl urea that inhibits C‐RAF kinase was discovered using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43‐9006 (Sorafenib, Nexavar®), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C‐RAF and B‐RAF (wild type and V600E mutant). It inhibited MEK and ERK phosphorylation in various cancer cell lines and tumor xenografts and exhibited potent oral antitumor activity in a broad spectrum of human tumor xenograft models. Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR‐2 and VEGFR‐3) and platelet‐derived growth factor receptor family (PDGFR‐β and Kit), which play key roles in tumor progression and angiogenesis. Thus, sorafenib may inhibit tumor growth by a dual mechanism, acting either directly on the tumor (through inhibition of Raf and Kit signaling) and/or on tumor angiogenesis (through inhibition of VEGFR and PDGFR signaling). In phase I and phase II clinical trials, sorafenib showed limited side effects and, more importantly, disease stabilization. This agent is currently being evaluated in phase III clinical trials in renal cell and hepatocellular carcinomas.

Biaryl Ureas as Potent and Orally Efficacious Melanin Concentrating Hormone Receptor 1 Antagonists for the Treatment of Obesity

Herein, we report a small molecule MCH-R1 antagonist which demonstrates oral efficacy in chronic rodent models. Substituted phenyl biaryl urea derivatives were synthesized and evaluated as MCH-R1 antagonists for the treatment of obesity. The structure-activity relationship studies in this series resulted in identification of urea 1 as a potent and selective MCH-R1 antagonist. Compound 1 exhibited oral efficacy in chronic (28 d) rodent models at 3-30 mpk showing significant reduction in food intake and weight gain relative to controls.

A phase II study of BAY 43–9006 in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) and nasopharyngeal cancer (NPC)

5566 Background: Bay 43–9006, a novel bi-aryl urea, is a potent inhibitor of kinases of Raf-1 (C-Raf) and B-Raf which are critical members of the RAS/RAF/MEK/ERK signalling pathway. In addition, Bay 43–9006 inhibits other pro-angiogenic protein tyrosine kinases, including VEGFR-2/3 and PDGFR-β. Overexpression of these signal transduction and angiogenic markers has been associated with poor prognosis in epithelial malignancies. We conducted a phase II study to examine the efficacy of Bay 43–9006 in advanced HNSCC and NPC. Methods: Patients (pts) with advanced HNSCC and NPC with measurable disease, no more than one prior chemotherapy regimen for recurrent and/or metastatic disease, performance status (PS) ECOG 0–2, and adequate organ functions were eligible. Bay 43–9006 was administered orally at 400 mg BID on a continuous basis, in 28-day cycles. Responses were evaluated every 8 weeks according to RECIST criteria. Results: Seventeen patients have been enrolled to date (9m/8f). Median age was 59 years (range 46 - 77); 82% had PS 0 or 1 and 18% PS 2; 65% HNSCC and 35% NPC; 11 pts had received prior chemotherapy, 3 had received prior erlotinib and 16 had received prior radiation therapy. All pts were evaluable for toxicity and 10 for response assessment to date. Six pts (60%) (4 HNSCC and 2 NPC) had stable disease ranging from 3 to 6 cycles, and 4 pts (40%) had progressive disease. A total of 36 cycles had been administered (median number/patient: 2; range 1–6). No grade 4 toxicity was seen. Main haematological toxicity was grade 3 lymphopenia in 5 (29%) pts. Common grade 3 non-hematological toxicity included hyponatremia in 4 (24%), dyspnea in 3 (18%), and non-specific pain in 3 (18%) pts. Grade 1/2 non-hematolgical toxicity included fatigue in 15 (88%), hypertension in 6 (35%), hand-foot syndrome in 6 (35%) and skin rash in 3 (18%) pts respectively. One pt died of intracranial tumoral hemorrhage, deemed to be unlikely related to treatment. Conclusions: Bay 43–9006 was well tolerated. Although no objective response was seen to date in this group of heavily pretreated patients, over half of the evaluable patients had achieved tumor stabilization. Further trial accrual is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer

BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.

The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.

Smart cleavage reactions: the synthesis of an array of ureas from polymer-bound carbamates.

The solid-phase synthesis of a library of di-, tri-, and tetrasubstituted ureas is described. In this approach, an array of polymer-bound carbamates was synthesized. These polymer-bound primary and secondary amine carbamates were then treated under "smart" diversity-building cleavage conditions using a series of aluminum amide complexes to form the corresponding urea cleavage products. The crude cleavage products from this study were isolated in excellent yield and purity. To show the applicability of this strategy, a series of biaryl ureas were synthesized using sequential solid-phase Suzuki coupling and urea formation reactions.