Kelvin Cooper

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.

Synthesis of a galactose-fucose disaccharide mimic of sialyl Lewis X

Abstract Disaccharide 4 was designed as a structurally simplified, potential mimic of sialyl Lewis X (1). 4 was prepared utilizing Schmidts trichloroacetimidate methodology in 10 linear steps from methyl galactoside 5. 4 exhibited activity in an E-selectin binding assay at concentrations 40 to 45-fold higher than that observed for monomeric sialyl Lewis X.

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.

The SAR of UK-78,282: a novel blocker of human T cell Kv1.3 potassium channels

Abstract UK-78,282 was identified in a human T cell 86Rb efflux high-throughput screen of our compound libraries. This compound was found to be a potent and selective blocker of human T cell voltage-gated K+ channels and to inhibit T cell activation. The SAR around UK-78,282 and a general pharmacophore hypothesis are presented in this communication.

Chapter 9. PAF Antagonists

Publisher Summary This chapter discusses the role of platelet activating factor (PAF) as a mediator of allergic disease and in cellular responses. The use of antagonists, in determining the biological significance of PAF, has also been discussed in the chapter with particular emphasis on asthma and ischemic states. The functional consequences of PAF antiagonist interaction with PAF receptors has been evaluated in various cell types and isolated tissues in vitro and in several organ systems in vivo . The efficacy of PAF antagonists in a variety of animal models, in which endogenous mediators are released, supports a major contributory role for PAF in several inflammatory and allergic pathophysiological conditions. Delayed bronchospasm, bronchial hyperreactivity, shock syndromes, ischemia and reperfusion injury, and transplant rejection has been discussed in the chapter. PAF can induce several functional responses in a variety of inflammatory cells. The pyridoquinazoline carboxamide inhibits both the acute bronchospasm and hypotension induced by intravenous PAF. There is much evidence supporting a role of PAF in models of several shock syndromes. In contrast to heart and lung, PAF-induced increases in vascular permeability of isolated rat kidney. The contribution of endogenous PAF to the damage caused by ischemia and reperfusion in several vascular beds has been discussed. PAF antagonists protect several specific organ systems from a variety of insults.

A stereoselective synthesis of the C(8)-C(20) fragment of premonensin B

Abstract Two stereoselective Ni(O)-catalysed coupling reactions of MeMgBr with cyclic enol ether intermediates were key steps in the synthesis of the C(8)-C(20) fragment ( 5B ) of Premonensin B.

The development of non-steroidal dual inhibitors of both human 5α-reductase isozymes

Abstract The design, synthesis and biological properties of homochiral non-steroidal inhibitors of both isozymes of human 5α-reductase are described. The o-hydroxy aniline moiety of the initial lead (1) can be replaced by a 3-acyl indole isostere, whilst the minimum energy conformation of the benzyl ether in the potent inhibitor (3) is mimicked by the conformationally locked benzodioxolane system in the potent non-steroidal inhibitor (7). Pharmacokinetics and oral efficacy in a rat model of BPH are presented for (3) and (7).

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.

An optically pure 1,4-dihydropyridine from a resolution catalysed by rabbit liver esterase

Abstract The kinetic resolution of a precursor of the dihydropyridine UK-74,505, 1 , an antagonist of platelet activating factor, is described, in which rabbit liver esterase was used to catalyse the hydrolysis of an ester function linked to the chiral centre via a spacer arm of appropriate length.

Dihydropyridines: a new class of angiotensin II antagonists

Abstract The syntheses and biological activities of dihydropyridine angiotensin II (AII) antagonists are described. Compounds such as 12 are examples of a new, structurally distinct class of AT(in1-selective agents.