Therapeutic Opportunities

The symptoms of many chronic diseases, such as rheumatoid arthritis, multiple sclerosis, asthma and chronic obstructive pulmonary disease (COPD) are caused in large part by an excessive and chronic inflammatory response and are therefore potential human diseases for drugs which inhibit the SSAO/VAP-1 activity. Notably, it has been recently shown that patients suffering from either atopic eczema or psoriasis, both chronic inflammatory skin disorders, demonstrate an increase in SSAO/VAP-1 positive vessels in their skin compared to skin from healthy controls [47,48]. 

In an important study, Kirton et al. [5] engineered a mouse-human chimeric antibody and demonstrated that this was able to reduce leukocyte migration in various in vitro and in vivo mouse models. In particular, leukocyte migration to the peritoneal cavity was reduced by 40% in the thioglycollate inflammation model using mice expressing human SSAO/VAP-1 protein. The Finnish company Biotie Therapies Corporation, is in clinical development with an antibody to VAP-1 [54], 

A group from La Jolla Pharmaceuticals has released data on their novel hydrazines in recent scientific [20,59,60] and patent literature [61,62], A series of arylallyl hydrazines (e.g., 8 and 9) were shown to be potent, irreversible inhibitors of rat and human SSAO/VAP-1 [59]. LJP-1207 (8, IC50 = 2nM, human) was evaluated in a series of in vivo inflammation models. Significant efficacy was observed in a mouse ulcerative colitis, mouse LPS-induced septic shock, and the rat carrageenan foot models [20], in a mouse model that resembles human multiple sclerosis [63], and in a transient forebrain ischemia model in estrogen-treated ovariectomized female rats [60]. 

Two laboratories have independently disclosed an interesting series of mechanism-based inhibitors. The dihydropyrrole 31, which appeared in a patent application [61], was reported to inhibit rat lung SSAO/VAP-1 with an IC50 = 500 nM. Recently, the Sayre team extended earlier work [74] and showed that these inhibitors, exemplified by 32, covalently bound to the enzyme with the cofactor in the reduced form [75]. Presumably, aromatization of the dihydropyrrole moiety accounts for the observed potencies. 

Novel structures are now appearing in the patent literature. A series of hydro-xamic acids, such as 33 (IC50 = lOOnM, human) were disclosed in a recent 

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Therapeutic opportunities for NO synthons include angina, for which nitroglycerin is effectively used, as well as penile erectile dysfunction. NOS inhibitors have demonstrated some protection in cerebral ischemia models and may be potentially beneficial in alleviating cell death associated with cerebral ischemia. l-NMA is under clinical study for treatment of sepsis. 

Shieh CC, Coghlan M, Sullivan JP et al (2000) Potassium channels molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev 52 557-594... 

The concept of drug development is based on the findings that retinoid receptors (RARs and RXRs) offer a new approach by targeting different genes depending on the activated retinoid receptor complexes. The multiplicity of these retinoid signaling pathways affords potential for therapeutic opportunity as well as retinoid therapy associated undesired side effects. It is possible that the indiscriminate activation of all pathways by nonspecific retinoid ligands could lead to unacceptable side effects so that any enhanced efficacy would be obtained at the cost of enhanced toxicity. 

Goutopoulos A, Makriyannis A From cannabis to cannabinergics new therapeutic opportunities. Pharmacol Ther 95 103—17, 2002... 

Protein Misfolding and Neurodegenerative Disease Therapeutic Opportunities... 

There is emerging evidence that VLDL assembly in general and MTP function in particular are intimately tied to assembly of hepatitis C virus (HCV) infectious particles [63]. MTP inhibition and ApoB downregula-tion in turn inhibit HCV assembly and maturation [64]. This may open new therapeutic opportunities for small-molecule MTP inhibitors in the... 

Pelletier, J., and Peltz, S. W. (2007). Therapeutic Opportunities in Translation. Cold Spring Harbor Laboratories, Cold Spring Harbor, NY. 

As indicated in the discussion of axotomy models, the beneficial influences of trophic factors on motor neurons provide potential therapeutic opportunities. Although previous human trials have been disappointing (for review see [111,112]), adenoassociated viral (AAv) delivery of insulinlike growth factor (IGF)-l to muscle prolongs survival in mutant SOD1 mice [111]. Thus, following intramuscular injection, the retrograde transport of AAV-IGF-1 appears to provide trophic influences to motor neurons. 

In this rapidly evolving field, the detection of PDE enzymes in the central nervous system (CNS) has stimulated interest in exploring potential applications of PDE inhibitors for treating CNS disorders such as Alzheimer s disease and other cognitive malfunctions, depression, anxiety, and schizophrenia. This review will focus on these therapeutic opportunities as well as new developments in the medicinal chemistry and biology associated with selected members of the PDE family, in particular PDEs 2, 4, 9, and 10. There have been a number of other reviews in this field in the past year that have covered selected individual PDE enzymes and potential pharmacologic applications of PDE inhibitors in CNS disorders [3,7,8]. 

Leutje CW, Patrick J (1991) Both a- and 3-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors, J Neurosci 11 837-845 Lindstrom J (1998) Purification and cloning of nicotinic acetylcholine receptors. In Americ SP, Brioni JD (eds) Neuronal nicotinic receptors pharmacology and therapeutic opportunities. Wiley, New York, pp 3-23... 

Eglen RM, Choppin A, and Watson N. Therapeutic opportunities from muscarinic receptor research. Trends Pharmacol Sci 2001 22 409 14. 

Flores, C. M., Hargreaves, K. M. Neuronal nicotinic receptors New targets in the treatment of pain, in Neuronal nicotinic receptors Pharmacology and therapeutic opportunities, edited by S. P. 

Auchampach JA, Bolli R (1999) Adenosine receptor subtypes in the heart Therapeutic opportunities and challenges. Am J Physiol 276 3 Pt 2 H1113-H1116... 

Buckbinder L, Robinson RP. The glucocorticoid receptor molecular mechanism and new therapeutic opportunities. Curr Drue Targets Inflamm Allergy. 2002 1 127-136. 

Rybak LP, Whitworth CA. Ototoxicity therapeutic opportunities. DrugDiscov Today. 2005 10 1313-1321. 

Fourth, the demonstration that many of these enzymes have prognostic value in cancer may qualify them as novel therapeutic targets. For example, similar to many other proteases, these enzymes may participate in the digestion of extracellular matrix, thus facilitating tumor invasion and metastasis. The identification of highly specific inhibitors may reveal new therapeutic opportunities. 

Schumacher M, Guennoun R, Stein DG, De Nicola AF (2007) Progesterone therapeutic opportunities for neuroprotection and myelin repair. Pharmacol Ther 116 77—106 Seldon HL (2007) Extended neocoitical maturation time encompasses speciation, fatty acid and laterahzation theories of the evolution of sdrizophtenia and creativity. Med Hypotheses 69(5) 1085-1089... 

Zeki, A. A., Kenyon, N.J., and Goldkorn, T. (2011). Statin drngs, metabolic pathways, and asthma a therapeutic opportunity needing further research. Drug Metab Lett 5 40-44. 

Serhan CN, Levy BD, Clish CB, Gronert K, Chiang N. Lipoxins, aspirin-triggered 15-epi-lipoxin stable analogs and their receptors in anti-inflammation a window for therapeutic opportunity. Ernst Sobering Res. Found Workshop 2000 143-185. 

Makriyannis A, Mechoulam R, Piomelli D. Therapeutic opportunities through modulation of the endocannabinoid system. Neuropharmacology 2005 48 1068-1071. 

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