HMR 1031 is a potent and specific antagonist of the integrin VLA-4 (alpha4beta1) binding to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin. HMR 1031 is an inhaled drug being developed for the treatment of asthma using an Ultrahaler dry-powder inhalation device. The interaction of VLA-4 with VCAM-1 is involved in the extravasations, activation, and extravascular survival of mononuclear leukocyte and eosinophil cell types at sites of airway inflammation. Thus, the VLA-4 antagonist, HMR 1031, has potential as an anti-inflammatory agent.

CP 99994 dihydrochloride have shown the compound to be a potent, selective and competitive NK-1 receptor antagonist. In preclinical studies, CP 99994 decreased cough number, peak abdominal activity, and peak tracheal pressure, without affecting baseline respiration. But in clinical trial administration of CP 99994 over 2 h does not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in subjects with mild asthma. CP 99994 significantly suppressed acute postoperative pain at 90 min after surgery.

L-N6-(1-iminoethyl)lysine 5-tetrazole amide (SC-51 or L-NIL-TA) is rapidly converted in vivo to the active metabolite L-N6-(1-iminoethyl)lysine (L-NIL). L-NIL is a relatively selective inhibitor of nitric-oxide synthase type 2 (NOS2). Unlike L-NIL, L-NIL-TA has minimal inhibitory activity in vitro on human NOS2. However, it is rapidly converted in vivo to L-NIL and produces dose-dependent inhibition of iNOS in acute and chronic models of inflammation in the rodent with efficacy comparable to L-NIL. L-NIL-TA produces marked inhibition of exhaled breath NO in normal and asthmatic subjects without producing the side effects observed following the systemic administration of non-selective NOS inhibitors, and thus provides support for the potential use of iNOS inhibitors to treat a range of inflammatory clinical disorders.

TR14035 (SB 683698) is a dual integrin alpha-4/beta-1 and alpha-4/beta-7 antagonist. Integrin alpha-4/beta-1 and alpha-4/beta-7 are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. It was originated by Tanabe Seiyaku and was being developed by Tanabe Research Laboratories and GlaxoSmithKline in Japan, the USA and Europe. TR 4035 was being developed in phase II clinical studies for the treatment of asthma and rheumatoid arthritis. It may also have had potential in a number of other inflammatory diseases, including inflammatory bowel disease and multiple sclerosis, for which it was at the phase I stage of clinical investigation. However, development has now been discontinued.

UCB35625 is a potential inhibitor of chemokine/eosinophil interactions. UCB35625 is a trans-isomer of a compound J113863, which was originally identified by scientists at Banyu Pharmaceutical Company as a candidate small molecule chemokine receptor antagonist. UCB35625 initially identified as CCR1 and CCR3 antagonists also bind to CCR2 and CCR5 and act as full agonist, partial agonist or antagonist according to the nature of the receptor and the signaling pathway investigated. UCB35625 shows promise as a lead compound for the design of future therapeutics, which may be of use in the treatment of allergic inflammatory diseases such as asthma and also the blockade of viral entry by HIV strains that utilize CCR3.

HC-030031 is a substituted theophylline derivative. Potent and selective TRPA1 inhibitor. HC-030031 inhibits human and rat TRPA1 with IC50 of 6.2 and 7.6 uM, respectively. It is selective against several TRP channels (IC50 >10 or 20 uM). HC-030031 can block both inward and outward currents elicited by AITC or formalin rapidly and reversibly and also blocks the activation of TRPA1 by N-methylmaleimide and by electrophillic prostaglandins. It does not block currents mediated by TRPV1, TRPV3, TRPV4 hERG, or NaV1.2 channels. HC-030031 exhibited efficacy in CFA, SNL, and other pain models. HC-030031 was shown to attenuate cold hyperalgesia in CFA (inflammatory), spared never injury (SNI, neuropathic), and paclitaxelmediated cold hyperalgesia. Also HC-030031 was found to decrease heat hyperalgesia in the paclitaxel model of chemotherapy-induced neuropathic pain.In an ovalbumin-induced mouse asthma model, gene KO and treatment with HC-030031 reduced the induction of cytokines, chemokines, neurotransmitters, as well as leukocyte infiltration and airway hyperactivity. Furthermore, HC-030031 and genetic deletion of mast cells attenuated itch-scratching behaviors. In oxazolone-induced contact dermatitis models, TRPA1 KO and HC-030031 decreased pro-inflammatory cytokines, T cell infiltration, dermatitis score, and edema, indicating that TRPA1 may play a central role in inflammation and pruritus.

PCI-34051 is a potent and specific HDAC8 inhibitor with IC50 of 10 nM in a cell-free assay. PCI-34051 inhibits ovarian tumor line OVCAR-3 with a GI50 of 6 μM and 15% cell death. Neither significant tubulin nor histone acetylation is observed in the sensitive cell lines treated with PCI-34051 at concentrations less than 25 μM at 24 hours nor at earlier timepoints. PCI-34051 induces a selective cytotoxic effect in cell lines derived only from T-cell malignancies. PCI-34051 induces caspase-dependent apoptosis. PCI-34051 undergoes preclinical studies for cancer

SB239063 is a potent and selective p38 mitogen-activated protein kinase (p38 MAPK) alpha/beta inhibitor with IC50 of 44 nM, showing no activity against the gamma and delta kinase isoforms. SB 239063 is a potent inhibitor of inflammatory cytokine production, inhibits eosinophil recruitment, in addition to enhancing apoptosis of these cells and it can use for the treatment of asthma and other inflammatory disorders.

BMS-509744 is a potent interleukin-2 inducible T cell kinase (ITK) inhibitor (IC50 = 19 nM). It displays 200-fold selectivity over Tec family kinases and 55-fold selectivity over other kinases tested. BMS-509744 reduces HIV infection of primary CD4+ T cells and attenuates the establishment of HIV infection in vitro. BMS-509744 also reduces T cell proliferation and IL-2 production in vitro. BMS-509744 reduces TCR-induced functions including PLCgamma1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion, and T-cell proliferation in vitro in both human and mouse cells. BMS-509744 suppresses the production of IL-2 induced by anti-TCR antibody administered to mice. BMS-509744 also significantly diminishes lung inflammation in a mouse model of ovalbumin-induced allergy/asthma.

BAY 61-3606 is a potent inhibitor of spleen tyrosine kinase (Syk) which is playing essential roles in receptors for Fc portion of immunoglobulins and B cell receptor complex signaling in various inflammatory cells. In addition, BAY61-3606 could inhibit the inhibitor of nuclear factor kappa B kinase (IKK-alpha) kinase activity. The compound is able to inhibit neoplastic phenotype of leukemia cells as well as of colon and breast cancer cells in vitro. BAY 61-3606 also exrets antiinflammatory and antiallergic properties in animal models.