Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotransmission, have been synthesized: monosubstituted 2-benzothiazolamines and 3-substituted derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent anticonvulsant activity against administration of glutamic acid in rats. The most active compounds displaying in vivo "antiglutamate" activity were the 6-OCF(3) (riluzole), 6-OCF(2)CF(3), 6-CF(3), and 6-CF(2)CF(3) substituted derivatives with ED(50) values between 2.5 and 3.2 mg/kg i.p. Among the second series of variously substituted benzothiazolines, compounds as active as riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a beta-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their corresponding sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and 2-imino-3-(2-methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED(50) = 1.0 and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the best benzothiazolines protected mice from mortality produced by hypobaric hypoxia.

Activation of the MET/HGF pathway is common in human cancer and is thought to promote tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies. We report here the pharmacologic characterization of the triazolopyridazine derivative SAR125844, a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK), for intravenous administration. SAR125844 displayed nanomolar activity against the wild-type kinase (IC 50 value of 4.2 nmol/L) and the M1250T and Y1235D mutants. Broad biochemical profiling revealed that SAR125844 was highly selective for MET kinase. SAR125844 inhibits MET autophosphorylation in cell-based assays in the nanomolar range, and promotes low nanomolar proapoptotic and antiproliferative activities selectively in cell lines with MET gene amplification or pathway addiction. In two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T, intravenous treatment with SAR125844 leads to potent, dose-and time-dependent inhibition of the MET kinase and to significant impact on downstream PI3K/AKT and RAS/MAPK pathways. Long duration of MET kinase inhibition up to 7 days was achieved with a nanosuspension formulation of SAR125844. Daily or every-2-days intravenous treatment of SAR125844 promoted a dose-dependent tumor regression in MET-amplified human gastric cancer models at tolerated doses without treatment-related body weight loss. Our data demonstrated that SAR125844 is a potent and selective MET kinase inhibitor with a favorable preclinical toxicity profile, supporting its clinical development in patients with MET-amplified and MET pathway-addicted tumors.

From an azaindole lead, identified in high throughput screen, a series of potent bis-azaindole inhibitors of IGF1-R have been synthesized using rational drug design and SAR based on a in silico binding mode hypothesis. Although the resulting compounds produced the expected improved potency, the model was not validated by the cocrystallization experiments with IGF1-R.Key words: drug discovery, enzyme structure, kinase, phosphatase, structure-based drug design Insulin-like growth factor (IGF) promotes growth and mediates metabolic signals (1). There is evidence that links IGF to cancer or tumorigenesis, and examination of the literature (2-5) from the last decade suggests that agents capable of inhibiting IGF receptor would have potential in the treatment of such malignancies (6). To date, the first results from clinical trials on antibodies or small molecules targeting IGF-1 receptor are starting to be reported and confirm these hypotheses (7). We now wish to report our own findings in this area.We initiated a high throughput screen (HTS) on IGF1-R using an Homogeneous Time-resolved Fluorescence (HTRF) assay relying on the receptor autophosphorylation. This led to the identification of a very potent hit 1 belonging to an azaindole chemical series from a Syk kinase inhibitor program (8).Me 1 IC 50 = 55 nMAs 1 was already quite potent on the target, we decided to evaluate it in an extensive panel of biological, Absorption, Distribution, Metabolism, Elimination (ADME), drug metabolism and Pharmacokinetics assays to anticipate potential liabilities and set the objectives of our optimization program.We first evaluated 1 in a series of secondary assays related to IGF function. The potency in an ELISA IGF1-R autophosphorylation assay was comparable to the one obtained in the HTRF assay. Compound 1 was also able to inhibit the IGF1-induced proliferation in two different cell lines, a Mouse Embryonic Fibroblasts (MEF) cell line engineered to over express IGF1-R and an MCF7 breast tumor cell line, with IC 50 's of 1.6 and 4.3 lM, respectively (Table 1).Selectivity against a panel of kinases was also evaluated. As expected because of its origin, 1 was a potent Syk inhibitor ( Table 2). As expected also because of its high homology, there was no selectivity versus insulin receptor kinase (IRK). Inhibitors of IRK would be expected to induce insulin resistance (hyperglycemia). It was hypothesized that for a short treatment period (about 4 months), there should not be any major metabolic disturbances (compared with the physiological insulin resistance during late state of pregnancy). In addition, some dual inhibitors of IGF1-R and IR-A such as 1H-Benzoimidazol-2-yl)-1H-pyridin-2-one BMS-536924 (9) are undergoing preclinical studies and could be advantageous for the treatment of tumours expressing both IGF1-R and IR-A (10). Finally, some inhibitors in development, such as the pyrrolo[2,3-d]pyrimidine NVP-AEW541 (11) displayed good selectivity for IGF1-R versus IR in intact cells in spite of no enzymatic selectivity for the kinas...

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The asymmetric oxidation of the disulfides (I) to give the thiosulfinates (II), of the sulfenamides (III) to form the sulfinamides (IV) and of the sulfenates (V) to yield the sulfinates (VI) is performed under the reaction conditions described.