Hiroko Masamune

Selective adenosine A3 receptor stimulation reduces ischemic myocardial injury in the rabbit heart

OBJECTIVE The aim of this study was to determine whether selective activation of the adenosine A3 receptor reduces infarct size in a Langendorff model of myocardial ischemia-reperfusion injury. METHODS Buffer-perfused rabbit hearts were exposed to 30 min regional ischemia and 120 min of reperfusion. Infarct size was measured by tetrazolium staining and normalized for area-at-risk (IA/AAR). RESULTS Preconditioning by 5 min global ischemia and 10 min reperfusion reduced infarct size (IA/AAR) to 19 +/- 4% (controls: 67 +/- 5%). Replacing global ischemia with 5 min perfusion of the rabbit A3-selective agonist, IB-MECA (A3 Ki: 2 nM; A1 Ki: 30 nM) elicited a concentration-dependent reduction in infarct size; 50 nM IB-MECA reduced IA/AAR to 24 +/- 4%. The A1-selective agonist, R-PIA (25 nM) reduced IA/AAR to a similar extent (21 +/- 6%). However, while the cardioprotective effect of R-PIA was significantly inhibited (54 +/- 7% IA/AAR) by the rabbit A1-selective antagonist, BWA1433 (50 nM), the IB-MECA-dependent cardioprotection was unaffected (28 +/- 6% IA/AAR). A non-selective (A1 vs. A3) concentration of BWA1433 (5 microM) significantly attenuated the IB-MECA-dependent cardioprotection (61 +/- 7% IA/AAR). CONCLUSIONS These data clearly demonstrate that selective A3 receptor activation provides cardioprotection from ischemia-reperfusion injury in the rabbit heart. Furthermore, the degree of A3-dependent cardioprotection is similar to that provided by A1 receptor stimulation or ischemic preconditioning.

Synthesis and in vitro profile of a novel series of catechol benzimidazoles. The discovery of potent, selective phosphodiesterase type IV inhibitors with greatly attenuated affinity for the [3H]rolipram binding site

Abstract The synthesis and biological properties of a novel series of potent and selective phosphodiesterase type IV (PDE IV) inhibitors are described. These catechol benzimidazoles were designed from rolipram and initial compounds reflected a similarly high affinity for the [ 3 H]rolipram b binding site (500 to 1000X greater affinity for the [ 3 H]rolipram binding site over the PDE IV inhibitory site). However, SAR studies on the 3-alkoxy position revealed that this [ 3 H]rolipram binding site affinity could be attenuated, while potentiating the PDE IV inhibitory activity. This resulted in the 2-indanyl analog 13 which is a potent, selective PDE IV inhibitor with a 15X differential in favor of PDE IV binding.

Discovery of micromolar PDE IV inhibitors that exhibit much reduced affinity for the [3H]rolipram binding site: 3-norbornyloxy-4-methoxyphenylmethylene oxindoles

Abstract The synthesis and the in vitro properties of a novel series of potent and selective phosphodiesterase type IV (PDE IV) inhibitors is described. Despite bearing structural similarity to rolipram, several of these compounds have much reduced affinity for the [3H]rolipram binding site.

Chapter 22. Cytokine Modulation as a Medicinal Chemistry Target

Publisher Summary This chapter summarizes the recent progress made in the discovery of modulators of cytokine function with the emphasis on the activity of small molecules and also discusses the clinical use of specific biologicals such as antibodies, soluble receptors, or recombinant cytokines. Interleukin 1 (IL-1), which plays a central role in both inflammatory and immunological responses and has been implicated in a wide range of human diseases, exis,ts in two different forms, IL-1α and IL-1β. Interleukin 2 (IL-2) plays an integral role in the clonal expansion of T-lymphocytes after antigen stimulation. In addition, it stimulates the growth and differentiation of a variety of other lymphocytes, including B cells, natural killer cells, and lymphokine-activated killer cells. The efficacy of IL-2 has been investigated in a number of cancerous states. Interleukin 3 is a 23 kDa glycoprotein, whose general function is to induce proliferation of early hematopoietic progenitor cells. Interleukin 4 is a 20 kDa peptide, which plays a key role in B-cell growth, and is the sole cytokine responsible for initiation of IgE synthesis, implicating it in allergic diseases and parasitic infections. Its immunoregulatory functions and potential application in cancer therapy have been reviewed. Interleukin 5 plays a key role in eosinophil and B-cell proliferation and differentiation. Interleukin 6 is a major mediator of the acute phase response to infection or injury. Interleukin 7 is a 25 kDa protein derived from stromal cells. It stimulates the proliferation of pre-B cells, thymocytes, and mature T cells. Interleukin 8 is a monocyte-derived chemotactic factor for neutrophils. Tumor necrosis factor-α plays a central role in host defense mechanisms and has been implicated in shock, chronic inflammation, and other autoimmune diseases. These studies can provide not only the pharmacological tools but also the future drugs for the treatment of immunological, inflammatory, and oncological diseases.

Chapter 19. Modulation of Arachidonic Acid Metabolism in the Treatment of Rheumatoid Arthritis

Publisher Summary This chapter describes the nonsteroidal anti-inflammatory drugs (NSAID) literature from late 1985 to the present and discusses the treatment of inflammatory diseases from the standpoint of biochemical interventions in the AA cascade. In-depth understanding of the underlying pathology has led to interest in the 5-lipoxygenase (5-LO) pathway of arachidonic acid (AA) metabolism, and hence cell chemoattractants, such as the leukotrienes (LT), as mediators of inflammatory diseases. Clinical studies continue to demonstrate the efficacy of this class against pain and inflammation. Studies have also shown that some carboxylic acid NSAlDs possess mechanisms of action beyond their classical CO pathway inhibition. Clinical studies continue to demonstrate the efficacy of this class against pain and inflammation. Studies have also shown that some carboxylic acid NSAlDs possess mechanisms of action beyond their classical CO pathway inhibition. Flunoxaprofen, one of the enantiomers, decreases the amount of thromboxane B 2 and PGE 2 , but not LTB 4 present in the inflammatory exudate provoked by carrageenin-soaked sponges implanted in rats. It also reduces the number of infiltrating inflammatory cells. In a small trial with osteoarthritic patients, it was effective in reducing pain and improving joint motility, while displaying minimal side effects. Cinmetacin, an indomethacin analog, shows improved toleration, possibly related to the fact that it binds to albumin more tightly than does indomethacin. Because the action of these phospholipase A 2 (PLA 2 ) and 5-LO/CO inhibitors more closely mimics to that of steroids on AA metabolism, these agents should in theory offer improved therapy over conventional NSAIDs. Furthermore, research into the role of other mediators, such as IL-1, has led to their identification as potential targets for drug intervention.

Synthesis and pharmacological profile of two novel heterocyclic chromanols, CP-80,798 and CP-85,958, as potent LTD4 receptor antagonists

Abstract The development of two novel LTD 4 receptor antagonists as clinical candidates for the treatment of asthma is described. The first generation compound, CP-80,798, was found to be a balanced 5-lipoxygenase inhibitor (5-LOI)/LTD 4 antagonist (LTD 4 -A), while the second generation compound, CP-85,958, is a selective LTD 4 antagonist.

Chapter 8. Novel Applications of Leukotriene Intervention

Publisher Summary This chapter discusses the pathogenic role for leukotrienes (LTs) in the lesser explored areas of disease. This perspective is limited to those LTs (5-HETE, LTB, LTC, LTD4, and LTE) that are synthesized from arachidonic acid (AA) via the 5-lipoxygenase (5-LO) pathway. In a study of 8 cluster headache patients, plasma levels of LTB4 have been found to be significantly elevated during an attack compared to the symptom-free periods. More recently, it has been reported that LTC 4 is detected in the plasma of migraine patients during the prodromal phase and in greater amounts during the beginning of the attack phase. Recent evidence strongly implicates LTs as significant factors in the pathophysiology of anaphylactic, endotoxic, and traumatic shock. In the presence of antihistamines, the selective 5-LOIs has been found to effectively block the ovalbumin-induced drop of coronary flow. Evidence, implicating the involvement of LTs in diseases of the kidney, has been discussed in the chapter. The most frequently mentioned renal disease suspected of being at least partly LT mediated is human glomerulonephritis. The upper gastrointestinal effects of LTs have been briefly described. Infusions of LTC 4 or LTD 4 significantly and dose-proportionally reduced gastric blood flow, gastric mucosal blood flow, gastric oxygen consumption, and acid output. The development of second generation 5-lipoxygenase inhibitors and antagonists of LTB 4 , LTC 4 , and LTD 4 , with extremely enhanced potency and selectivity, offers the promise of new insights into the contributions of leukotrienes to the pathophysiology of these diseases.

The discovery of CP-96,021 and CP-96,486, balanced, combined, potent and orally active leukotriene D4 (LTD4)/platelet activating factor (PAF) receptor antagonists.

The combination of key structural pharmacophores found in known leukotriene D4 (LTD4) receptor antagonists with those of potent platelet activating factor (PAF) receptor antagonist UK-74,505 has led to the synthesis of hybrid compounds CP-96,021 and CP-96,486. These compounds represent the first known balanced, combined and orally active LTD4/PAF receptor antagonists.

Synthesis and in vitro profile of 7-substituted quinoline chromanols as novel, non-acidic LTB4 antagonists

Abstract The development of novel LTB 4 antagonists from a class of quinolylmethyl LTD 4 antagonists is described. These α-methyl quinolylmethyl chromanols were found to have good vitro activity.

LTD4 Receptor binding activity of novel pyridine chromanols: qualitative correlation with pKa

Abstract A series of pyridine chromanols were synthesized and evaluated as LTD 4 -antagonists (LTD 4 -A). The quinoline sidechain of this class of such agents, as exemplified by REV-5901, has until now been deemed as essential for potent activity. However, by manipulating substituents on a pyridine ring, quinoline-like potency can be achieved. The results indicate that this is a function of pKa.