Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase isoenzymes, and their biosynthesis is blocked by nonsteroidal antiinflammatory drugs, including those selective for inhibition of cyclooxygenase-2. Despite the clinical efficacy of nonsteroidal antiinflammatory drugs, prostaglandins may function in both the promotion and resolution of inflammation. This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm.

Prostaglandins and Inflammation

We have developed a method to image tumor-associated lysosomal protease activity in a xenograft mouse model in vivo using autoquenched near-infrared fluorescence (NIRF) probes. NIRF probes were bound to a long circulating graft copolymer consisting of poly-L-lysine and methoxypolyethylene glycol succinate. Following intravenous injection, the NIRF probe carrier accumulated in solid tumors due to its long circulation time and leakage through tumor neovasculature. Intratumoral NIRF signal was generated by lysosomal proteases in tumor cells that cleave the macromolecule, thereby releasing previously quenched fluorochrome. In vivo imaging showed a 12-fold increase in NIRF signal, allowing the detection of tumors with submillimeter-sized diameters. This strategy can be used to detect such early stage tumors in vivo and to probe for specific enzyme activity.

In vivo imaging of tumors with protease-activated near-infrared fluorescent probes.

Artificial Organic Host Molecules for Anions

Maintaining research and development (R&D) productivity at a sustainable level is one of the main challenges currently facing the pharmaceutical industry. In this article, we discuss the results of a comprehensive longitudinal review of AstraZeneca's small-molecule drug projects from 2005 to 2010. The analysis allowed us to establish a framework based on the five most important technical determinants of project success and pipeline quality, which we describe as the five 'R's: the right target, the right patient, the right tissue, the right safety and the right commercial potential. A sixth factor - the right culture - is also crucial in encouraging effective decision-making based on these technical determinants. AstraZeneca is currently applying this framework to guide its R&D teams, and although it is too early to demonstrate whether this has improved the company's R&D productivity, we present our data and analysis here in the hope that it may assist the industry overall in addressing this key challenge.

Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework

On allergic rhinitis

Various N-sulfonylamino acid derivatives were synthesized and evaluated for their in vitro and in vivo activities to inhibit type IV collagenase (MMP-9 and MMP-2). When the amino acid residue and the sulfonamide moiety were modified, their inhibitory activities were greatly affected by the structure of the sulfonamide moiety. A series of aryl sulfonamide derivatives containing biaryl, tetrazole, amide, and triple bond were found to be potent and highly selective inhibitors of MMP-9 and MMP-2. In addition, these compounds were orally active in animal models of tumor growth and metastasis. These results revealed the potential of the N-sulfonylamino acid derivatives as a new type of candidate drug for the treatment of cancer.

Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives.

Phospholipase A2 is an enzyme which hydrolyzes the sn-2 position of certain cellular phospholipids. The liberated lysophospholipid and arachidonic acid are precursors in the biosynthesis of various biologically active products. As human nonpancreatic sPLA2 is present in high levels in the blood of patients in several pathological conditions, the potent sPLA2 inhibitors have been suggested to be useful drugs. Here we describe the synthesis, structure-activity relationship, and inhibitory activities of indolizine and indene derivatives. 1-(Carbamoylmethyl)indolizine derivatives and 1-oxamoylindolizine derivatives exhibited very potent inhibitory activity. The former was unstable to air oxidation, but the latter exhibited an improvement both in stability and in potency. Some compounds approached the stoichiometric limit of the chromogenic assay.

Potent inhibitors of secretory phospholipase A2: synthesis and inhibitory activities of indolizine and indene derivatives

Prostaglandin (PG) D2, the major cyclooxygenase metabolite generated from immunologically stimulated mast cells, is thought to contribute to the pathogenesis of allergic diseases due to its various inflammatory effects. However, since no DP receptor antagonist has been developed as an antiallergic drug, the role of PGD2 in the pathogenesis of allergic diseases remains uncertain. Here, we report the in vivo efficacy of our newly established DP receptor antagonist, S-5751 [((Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxy benzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5- enoic acid)], using various allergic inflammation guinea pig models. In allergic rhinitis models, oral administration of S-5751 dramatically inhibited not only early nasal responses, as assessed by sneezing, mucosal plasma exudation, and nasal blockage, but also late responses such as mucosal plasma exudation and eosinophil infiltration. Even when S-5751 was administered after recovery from the early responses, these late phase responses were almost completely suppressed. In addition, S-5751 alleviated allergen-induced plasma exudation in the conjunctiva in an allergic conjunctivitis model and antigen-induced eosinophil infiltration into the lung in an asthma model. These findings provide evidence for the crucial role of PGD2 as a mediator of allergic inflammation in guinea pigs and suggest that DP receptor antagonists may be useful in the treatment of allergic diseases triggered by mast cell activation.

Prevention of Allergic Inflammation by a Novel Prostaglandin Receptor Antagonist, S-5751

Pyrrolidine inhibitors of human cytosolic phospholipase A(2).

Compounds having a metalloproteinase inhibitory activity, represented by the formula (I), its optically active isomers, their pharmaceutically acceptable salts, or hydrates thereof.

Mitsuaki Ohtani

Papers

Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives.

Potent inhibitors of secretory phospholipase A2: synthesis and inhibitory activities of indolizine and indene derivatives

Prevention of Allergic Inflammation by a Novel Prostaglandin Receptor Antagonist, S-5751

Pyrrolidine inhibitors of human cytosolic phospholipase A(2).

Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same