With a favorable spectrum of CRTh
With a favorable spectrum of CRTh2 dependent in vitro and in vivo efficacy demonstrated, the off-target activity of compound 18 was investigated, first against a panel of prostanoid receptors and related eicosanoid targets (Table 8), where no significant activities at 10μM concentration were found in all cases. In a broader selectivity panel of 86 receptors and ion channels (including hERG) and 26 kinases conducted within Novartis and externally at MDS (now Ricerca; Spectrum Screen™) no hits were found after screening at a single 10μM concentration. The exquisite selectivity of this molecule was further confirmed by the lack of activity (IC50 >100μM) against human CYP1A2, CYP2C9, CYP2D6 and CYP3A4 isoforms and in a PXR based CYP3A4 induction assay a similar lack of activity was exhibited. The latter data indicates a low potential for cytochrome P450 mediated drug-drug interactions involving 18 in the clinical context.
Conclusion Further optimization of a 7-azaindole-3-acetic U 73343 chemotype derived from HTS delivered a new sub-series of selective CRTh2 receptor antagonists. Exploiting observations from the earlier sulfonamide sub-series, where lipophilicity reduction led to improved eosinophil SC potency, compound 18 showing low nM potency and excellent selectivity across a range of CRTh2 dependent primary human inflammatory cell assays was discovered. This molecule showed good pharmacokinetic properties (including a suitable escalating dose–exposure relationship) in the rat and mouse and was efficacious in both mechanistic and allergic disease CRTh2-dependent rodent in vivo models. Based on the totality of this data package, 18 was advanced into preclinical development and designated NVP-QAV680. A favorable GLP toxicology profile in rats and dogs for NVP-QAV680 facilitated progression of the molecule into single and muliple ascending dose healthy volunteer Phase 1 studies, followed by a human allergy Proof of Concept (PoC) clinical study, the details of which will be reported elsewhere in due course.
Experimental LCMS were recorded using an Agilent 1100 LC system with Waters Xterra MS C18 4.6×100 5μM column, eluting for 10min with gradient of 5–95% MeCN in water (10mM ammonium bicarbonate or 0.1% trifluoroacetic acid used as buffer). Unless indicated otherwise, all final compounds were purified to ⩾95% purity as determined by high performance liquid chromatography (HPLC) with UV detection at 254 and 220nm, together with ELSD. All 1H NMR spectra were obtained on either a Bruker AV400 or a Bruker DRX500 spectrometer operating at 400 and 500MHz, respectively, both at 298K.
Introduction Obesity is now a serious global problem , which is associated with the metabolic diseases such as hypertension, dyslipidemia, and type 2 diabetes , , . Most of these diseases can be prevented or ameliorated by reducing body weight. Thus, the control of obesity is critical for not only healthcare, but also health economics. Several anti-obesity drugs have been used over the years; however, most of these drugs have been withdrawn because they often have serious side effects . Therefore, the elucidation of the molecular mechanism underlying obesity (adipogenesis) is essential for the development of anti-obesity drugs. Adipocytes play critical roles in the maintenance of energy balance in the body through the control of fat storage and hydrolyzing triglycerides (TGs) . Adipose TG is hydrolyzed into free fatty acids and glycerol through sequential hydrolysis-reactions of three lipases; adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL) . HSL is one of the rate-limiting enzymes in the TG-hydrolysis pathway (lipolysis). HSL activity is regulated via the phosphorylation of several serine residues . β-Adrenergic agonists activate HSL and increase its activity through the protein kinase A (PKA)-mediated phosphorylation of serine at position 563 (Ser563) . Moreover, HSL is translocated from the cytosols to the surface of lipid droplets through the phosphorylation of another serine residues in HSL . In addition, insulin inhibits lipolysis through Akt-mediated suppression of PKA activity, followed by the suppression of activation of HSL.