Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. The data reveal that the combination of excellent potency, selectivity, and pharmacokinetic properties is unique to AC220, which therefore is the first drug candidate with a profile that matches the characteristics desirable for a clinical FLT3 inhibitor. (Blood. 2009; 114:2984-2992) IntroductionThe presence of genetic changes in cancer cells that lead to dysregulated activation of kinases frequently signals that the activated kinase is a contributing driver of disease, 1-4 and inhibitors of activated kinases can have a dramatic impact on disease progression in patients with these genetic alterations. 5,6 To clearly define the role of the dysregulated kinase, and to determine whether inhibition of the mutant kinase is sufficient to induce a therapeutic benefit, requires drugs capable of selectively, potently, and preferably sustainably inhibiting the activated kinase in patients.Activating mutations in the FLT3 receptor tyrosine kinase have been identified in up to 30% of acute myeloid leukemia (AML) patients. 7,8 The most common class of mutation is internal tandem duplications (ITDs) in the juxtamembrane domain 7,9 that lead to constitutive, ligand-independent activation of the kinase. 7,10 The prognosis for patients with FLT3-ITD mutations is significantly worse than that for patients with wild-type FLT3 when treated with standard therapy. [7][8][9][11][12][13][14][15][16] The presence of activating FLT3 mutations and the correlation of FLT3 activation with a poor prognosis strongly suggest that FLT3 is a driver of disease in AML, at least in patients with FLT3-ITD mutations. Several small molecule kinase inhibitors with activity against FLT3 have been evaluated in AML patients, including CEP-701 (lestaurtinib), PKC-412 (midostaurin), MLN-518 (tandutinib; previously known as CT-53518), sunitinib (SU-11248), sorafenib , and KW-2449. The compounds inhibit FLT3 in cellular assays and are efficacious in mouse models of FLT3-ITD AML. [17][18][19][20][21][22] In phase 1 and phase 2 clinical trials, conducted primarily in relapsed or refractory AML patients, responses were consistently observed with each of these drugs, 21,[23][24][25][26][27][28][29][30][31] however, responses generally were relatively limited and not durable. 21,[23][24][25]30 The studies did reveal a relationship between the likelihood of observing a clinical response and the pharmacokinetics/pharmacodynamics of FLT3 inhibition, and highlight...

Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharmacokinetics (PK) or lack of adequate tolerability at efficacious doses. We have developed a series of extremely potent and highly selective FLT3 inhibitors with good oral PK properties. The first series of compounds represented by 1 (AB530) was found to be a potent and selective FLT3 kinase inhibitor with good PK properties. The aqueous solubility and oral PK properties at higher doses in rodents were found to be less than optimal for clinical development. A novel series of compounds were designed lacking the carboxamide group of 1 with an added water solubilizing group. Compound 7 (AC220) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. Compound 7 has demonstrated a desirable safety and PK profile in humans and is currently in phase II clinical trials.

A series of isoquinolin-1-ones and quinazolin-4-ones and related derivatives were prepared and evaluated for their ability to inhibit tumor necrosis factor alpha (TNFalpha) production in human peripheral blood monocytes stimulated with bacterial lipopolysaccharide (LPS). In an effort to optimize the TNFalpha inhibitory activity, a homologous series of N-alkanoic acid esters was prepared. Several electrophilic and nucleophilic substitutions were also carried out. Alkanoic acid esters of four carbons were found to be optimum for activity in both the isoquinoline and quinazoline series. Ring substituents such as fluoro, bromo, nitro, acetyl, and aminomethyl on the isoquinoline ring resulted in a significant loss of activity. Likewise, similar groups on the quinazoline ring also reduced inhibitory activity. However, the 6- and 7-aminoquinazoline derivatives, 75 and 76, were potent inhibitors, with IC(50) values in the TNFalpha in vitro assay of approximately 5 microM for each. An in vivo mouse model of pulmonary inflammation was then used to evaluate promising candidate compounds identified in the primary in vitro assay. Compound 75 was selected for further study in this inhalation model, and was found to reduce the level of TNFalpha in brochoalveolar lavage fluid of LPS-treated mice by about 50% that of control mice. Thus, compounds such as 75, which can effectively inhibit proinflammatory cytokines such as TNFalpha in clinically relevant animal models of inflammation and fibrosis, may have potential as new antiinflammatory agents. Finally, a quinazoline derivative suitable to serve as a photoaffinity radiolabeled compound was prepared to help identify the putative cellular target(s) for these TNFalpha inhibitors.

A new and convenient method for the construction of sulfonamides via a copper-catalyzed oxidative coupling between sodium sulfinates and amines with 1 atm O2 or DMSO as the oxidant was described. This method provides efficient and robust synthesis of functional sulfonamides in good yields and excellent chemoselectivity. And detailed mechanistic studies showed that this transformation may go through a single electron transfer (SET) pathway.

Inspired by the idea of Bonferroni mean, in this paper we develop an aggregation technique called the interval-valued intuitionistic fuzzy Bonferroni mean for aggregating interval-valued intuitionistic fuzzy information. We study its properties and discuss its special cases. For the situations where the input arguments have different importance, we then define a weighted interval-valued intuitionistic fuzzy Bonferroni mean, based on which we give a procedure for multi-criteria decision making under interval-valued intuitionistic fuzzy environments.

Three polystyrene-supported N-heterocyclic carbene-silver complexes [PS-NHC-Ag(I)] and a polystyrene-supported N-heterocyclic carbenecopper complex [PS-NHC-Cu(I)] catalyst were synthesized and characterized by elemental analysis, Fourier transform infrared spectroscopy, inductively coupled plasma-atom emission spectrometer, thermogravimetric analysis and scanning electron micrographs. The catalytic activity of the supported catalysts was investigated for the reaction of propargylic alcohols and carbon dioxide. PS-NHC-Cu(I) showed no catalytic activity to the reaction, while PS-NHC-Ag(I) showed a considerable high activity and selectivity for the reaction, yielding the corresponding a-alkylidene cyclic carbonates in high to excellent yields under mild conditions. Most importantly, the supported catalysts could be separated easily from the products and reused up to 15 times without loss of their high catalytic activity, showing excellent stability. The effect of various reaction parameters such as carbon dioxide pressure, temperature, time, and catalyst loading on the reaction was also investigated.

A regio- and stereoselective synthesis of sulfones and thioethers by means of Cu(I)-catalyzed aerobic oxidative N-S bond cleavage of sulfonyl hydrazides, followed by cross-coupling reactions with alkenes and aromatic compounds to form the C sp 2-S bond, is described herein. N2 and H2O are the byproducts of this transformation, thus offering an environmentally benign process with a wide range of potential applications in organic synthesis and medicinal chemistry.

A facile type of one-pot, transition-metal-free domino process was developed for the synthesis of oxazoles. Thus, a variety of polysubstituted oxazoles were easily synthesized via t-BuOOH/I(2)-mediated domino oxidative cyclization from readily available starting materials under mild conditions.