Using knowledge of the substrate specificity of cPLA(2) (phospholipases A(2)), a novel series of inhibitors of this enzyme were designed based upon a three point model of inhibitor binding to the enzyme active site comprising a lipophilic anchor, an electrophilic serine "trap", and an acidic binding moiety. The resulting 1,3-diheteroatom-substituted propan-2-ones were evaluated as inhibitors of cPLA(2) in both aggregated bilayer and soluble substrate assays. Systematic variation of the lipophilic, electrophilic, and acidic groups revealed a well-defined structure-activity relationship against the enzyme. Optimization of each group led to compound 22 (AR-C70484XX), which contains a decyloxy lipophilic side chain, a 1,3-diaryloxypropan-2-one moiety as a unique serine trap, and a benzoic acid as the acidic binding group. AR-C70484XX was found to be among the most potent in vitro inhibitors of cPLA(2) described to date being more than 20-fold more active against the isolated enzyme (IC(50) = 0.03 microM) than the standard cPLA(2) inhibitor, arachidonyl trifluoromethyl ketone (AACOCF(3)), and also greater than 10-fold more active than AACOCF(3) against the cellular production of arachidonic acid by HL60 cells (IC(50) = 2.8 microM).

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Matrilysin or matrix metalloproteinase 7 (MMP7) is a member of a class of zinc-dependent endopeptidases (MMPs) capable of degrading extracellular matrix proteins and thought to play an important role in tissue remodeling associated with various physiological and pathological processes. It has broad specificity and cleaves a number of matrix substances, including proteoglycans and collagen III/IV/V/IX/X/XI, [1] which underlies a potential role for MMP7 inhibitors in the treatment of disease associated with tissue degradation/remodeling. In addition, MMP7 has been reported to have a potential role in tumor metastasis and inflammatory processes.[2] It has also been reported to be expressed in osteoarthritic cartilage, where it is colocalized with the tetraspanin, CD151, which has been implicated in its pericellular activation. [3] As a class, MMPs have been the subject of intense study within the pharmaceutical industry over the last decade, and inhibitors have been described for many of the individual MMPs. [4][5][6] However, MMP selectivity remains a significant hurdle for most MMP inhibitors due to a reliance on zinc chelation to provide a significant component of the binding energy. Despite high therapeutic value, there has been a consistent lack of success with such inhibitors in the clinic, and this can largely be attributed to several factors: poor selectivity, poor target validation for the targeted therapy, and poorly defined predictive preclinical animal models for safety and efficacy. The selectivity problem is particularly true with compounds bearing groups that chelate strongly to zinc (e.g., hydroxamate, reverse hydroxamate) because a large component of the binding energy is derived from a feature common to all MMPs.With this in mind, we initiated a program to identify selective MMP7 inhibitors employing a high-throughput screening approach, with MMP selectivity assessment very early in the screening process. To provide an initial indication of selectivity, actives were screened against MMP1 and MMP14. Compounds showing good selectivity against these two MMPs were then screened against MMP2, MMP12 and MMP13 to give an indication of wider MMP selectivity. As anticipated, potent hydroxamate and reverse hydroxamate inhibitors were identified but none of them showed selectivity over other MMPs. In fact, without exception, hydroxamate, reverse hydroxamate and also hydantoin inhibitors proved more active against many of the other MMPs than against MMP7. One active hit that emerged from these initial selectivity screens was the carboxylic acid compound I.[7] The compound has low potency against MMP7, but there was no indication of activity against any of the other MMPs tested. The low potency limited a true assessment of selectivity but, nonetheless, this initial lead was pursued further, driven largely by two factors: ease of synthesis and crystallization. Firstly, we were able to successfully crystallize this compound within the MMP7 protein and determine the complex structure to enable an understanding of ...

Nedocromil sodium inhibited the bronchoconstriction caused by antigen challenge in Ascaris‐sensitive monkeys and in addition it prevented the release of histamine from mast cells lavaged from sensitive monkeys. Sodium cromoglycate was relatively inactive in both these systems. It is suggested that nedocromil sodium can stabilize both mucosal and connective tissue mast cells and may represent a new type of drug.

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Indium(II1) iodide forms both 1: 1 and 1 :2 adducts with triphenylphosphine, depending on the reaction conditions, and especially on the solvent used. The complex In13.PPh3 involves four-coordination at indium; the structure is trigonal, with a = 15.105(4) A, c = 16.769(7) A, V = 3313(2) A3, Z = 6, and space group ~3 .Crystals were also obtained in which In13. PPh3 and In13(PPh3), are present in a 1: 1 ratio; these are also trigonal, a = 15.473(4) A, c = 41.701(7) A, V = 8646.1(1.8) A3, Z = 3 + 3 and space ~3 .The 1:2 adduct has approximately D3,, symmetry in the In13P2 kernel. The bond distances and angles are discussed; in particular, the In-P bonds are extremely weak in the 1:2 adduct. This compound has been shown by 3 1~ NMR to undergo complete dissociation in solution to In13.PPh3 and PPh,. The addition of R4NI (R = n-C3H7, n-C4Hg) causes quantitative conversion to Id4-and free Ph,P. Similar experiments are reported for the compound In13(dppe) (dppe = 1,2-bis(diphenylphosphino)ethane), whose structure is an infinite chain of InI, units linked through In-P-C2H4-P-In coordination. The crystal structure showed that InI,(dppe) cocrystallizes with an equimolar quantity of dppe; these crystals are cubic, a = 41.445 (14)

Two photosensitive hydrophobic probes, azido [3H]benzene and 1-azido-4-iodo[3H]-benzene, have been compared for their effectiveness in labelling, selectively, the intramembranous domains of lipid and proteins. Both partition preferentially into the lipid bilayer and, upon irradiation, covalently attach to both phospholipids and membrane proteins; the more extrinsic polypeptides have a significantly lower specific radioactivity than that of the intrinsic species. Proteolytic experiments also reveal higher labelling of intramembranous regions of the proteins. Consistently, the iodinated form of the probe showed the greater preference for the non-polar phase and a higher degree of selectivity for labelling hydrophobic regions. The results also suggest that penetration through the annulus of tightly bound lipid surrounding integral proteins occurs readily.