Autotaxin catalyzes the transformation of lyso-phosphatidylcholine in lyso-phosphatidic acid (LPA). LPA is a phospholipid possessing a large panel of activity, in particular as a motility factor or as a growth signal, through its G-protein coupled seven transmembrane receptors. Indirect evidence strongly suggests that autotaxin is the main, if not the only source of circulating LPA. Because of its central role in pathologic conditions, such as oncology and diabetes/obesity, the biochemical properties of autotaxin has attracted a lot of attention, but confirmation of its role in pathology remains elusive. One way to validate and/or confirm its central role, is to find potent and selective inhibitors. A systematic screening of several thousand compounds using a colorimetric assay and taking advantage of the phosphodiesterase activity of autotaxin that requires the enzymatic site than for LPA generation, led to the discovery of a potent nanomolar inhibitor, [4-(tetradecanoylamino)benzyl]phosphonic acid (S32826). This compound was inhibitory toward the various autotaxin isoforms, using an assay measuring the [ 14 C]lyso-phosphatidylcholine conversion into [ 14 C]LPA. We also evaluated the activity of S32826 in cellular models of diabesity and oncology. Nevertheless, the poor in vivo stability and/or bioavailability of the compound did not permit to use it in animals. S32826 is the first reported inhibitor of autotaxin with an IC 50 in the nanomolar range that can be used to validate the role of autotaxin in various pathologies in cellular models.

The first example of the enantioselective methyl C-H activation by an intramolecular ArPdX species and subsequent cyclisation was developed. Palladium catalysts using commercially available chiral diphosphines yield good ee's (up to 93% ee) in the synthesis of 2-methyl indolines from 2-halo N-isopropyl anilides. This approach was also employed for the synthesis of enantioenriched cyclohexyl fused indolines with moderate enantioselectivities.

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET-and FGFR2-dependent gastric cancer cells, blocked METdriven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors.

Recently, we reported the synthesis of 3-(sulfonylamino)-2(1H)-quinolones, a new series of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate and N-methyl-D-aspartic acid (NMDA)/glycine antagonists. By exploring the structure-activity relationships (SAR) in this series, we were able to identify the 6,7-dinitro derivative 6 as a potent and balanced antagonist at both receptors. Unfortunately, compound 6 was devoid of in vivo activity in mice anticonvulsant testing. To overcome this critical limitation, new compounds bearing various acidic moieties at the 3-position of the quinolone skeleton were synthesized and evaluated. The SAR of these new analogues indicated that not all acidic groups are acceptable at the 3-position: A rank order of potency going from carboxylic approximately phosphonic > tetrazole > mercaptoacetic > hydroxamic >> other heterocyclic acids was defined. In addition, the selectivity between the AMPA/kainate and NMDA/glycine sites is dependent on the nature of the substitution (nitro > chloro for AMPA selectivity), its position (5,7- > 6,7-pattern for glycine selectivity), and the distance between the quinolone moiety and the heteroatom bearing the acidic hydrogen (the longer the distance the more AMPA selective the compound). Among these new AMPA antagonists, we have identified 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid (24c) as a water soluble and selective compound endowed with an appealing pharmacological profile. Compared with the reference AMPA antagonist NBQX, the phosphonic acid 24c is much less potent in vitro but almost equipotent in vivo in the audiogenic seizures model after intraperitoneal administration. Moreover, unlike NBQX, compound 24c is also active after oral administration. In the gerbil global ischemia model, compound 24c shows a neuroprotective effect at 10 mg/kg/ip, equivalent to the reference NBQX.

This is the first study showing that chronic treatment with an iNOS inhibitor, L-NIL, limits progression of preexisting atherosclerosis in hypercholesterolemic rabbits. Increased intimal collagen accumulation may participate in iNOS-induced atherosclerosis progression.