Small-molecule antagonists

Potent and Selective Small Molecule Antagonists of ol4/31 Integrins... 

Therapeutics A number of potent small molecule antagonists for av 33 integrin are under preclinical investigations for various angiogenesis or vascular-mediated disorders [10]. 

At present, two conceptually different (but not mutually exclusive) therapeutic strategies are being pursued in the vanilloid field one is to use optimized TRPVl agonists to desensitize (in practice, defunctionalize) capsaicin-sensitive nerves [1, 21] and the other is to employ small molecule antagonists for the pharmacological blockade of TRPVl [7, 8]. The first approach is time-proven, but is riddled by known side-effects such as pain [1], as well as emerging concerns such as impaired control of cancerous growth [22]. 

Rubin JB, Kung AL, Klein RS, et al. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci U S A 2003 100 13513-8. 

Sabroe I, Peck MJ, Van Keulen BJ, et al. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J Biol Chem 2000 275(34) 25985-25992. 

Widdowson KL, Elliott JD, Veber DF, et al. Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor. J Med Chem 2004 47(6) 1319-1321. 

Other clinical trials with CCR2 antagonists are underway [1], but no reports have been forthcoming. Both MLN-1202, a humanized anti-CCR2 antibody, and MK-0812, a small molecule antagonist, were examined in rheumatoid arthritis (vide supra) and are also being examined in multiple sclerosis. Two additional small molecules - CCX-915 and INCB-8696 - have entered phase 1 trials with multiple sclerosis as a projected phase 2 trial. An intention to study INCB-8696 in systemic lupus erythematosus has also been declared. Finally, phase 2 clinical... 

Multiple new series of CCR2 small molecule antagonists have been described in the recent patent and peer-reviewed literature. Importantly, the diversity of structural classes recognized as CCR2 antagonists has increased. These chemical advances should allow the scientific community to test adequately the hypothesis that CCR2 plays a key role in human inflammatory disease. 

Smith, S., Zhang, C., LaRosa, G., Jaffee, B., Yang, H., Eddy, P., Lu, C., Uttamsingh, V., Horlick, R., Harriman, G. and Flynn, D. (2006) Design, synthesis, and progress toward optimisation of potent small molecule antagonists of CC chemokine receptor 8 (CCR8). Journal of Medicinal Chemistry, 49, 2669-2672. 

Braisted, A.C., Hyde, J., McDowell, R.S., Randal, M., Waal, N.D., Wilkinson, J., Yu, C.H., Arkin, M.R. Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2 an approach for inhibiting protein-protein... 

Although in the early 1990s several antibodies were developed that inhibited leukocyte-endothelial cell interaction to prevent e.g. allograft rejection or inflammatory processes [72], more effort is nowadays put into the development of small molecule antagonists and antisense oligonucleotides for this purpose [73,74], A selection of more recently reported clinical studies with antibodies is summarized in Table 1.2. 

K. B. Bacon, An orally bioavailable small molecule antagonist of CRTH2, ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil migration in vitro, J. Pharmacol. Exp. Then 305 (2003) 347. 

For many of the neuropeptides the receptors are known, and more recently non-peptidic, small-molecule antagonists have become available. Application of these antagonists will help to elucidate further the involvement of peptidic neurotransmitters within the nervous system, as well as their contribution to mental disturbances. It is also expected that some of the recently developed antagonists may become useful therapeutic agents. 

Nemeth, E and Scarpa, A, 1987, Rapid mobilization of cellular Ca2+ in bovine parathyroid cells by external divalent cations, J Biol Chem 202 5188-5196 Nemeth, EF, Fox, J, Delmar, EG, Steffey, ME, Lambert, LD, Conklin, RL, Bhatnagar, PK and Gowen, M, 1998a, Stimulation of parathyroid hormone secretion by a small molecule antagonist of the calcium receptor., J Bone Miner Res 23 S156 (absract 1030)... 

Small molecule antagonists have been used to obtain important insights into the conformational regulation of integrin structure and function (Shimaoka and Springer, 2003). The ability of ligands and ligand-mimetic... 

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