A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E(2) receptors evaluated. Many of them are very potent and selective EP(3) antagonists (K(i) 3-10 nM), while compound 9 is a very good and selective EP(2) agonist (K(i) 8 nM). The biological profile of the EP(2) agonist 9 in vivo and the metabolic profile of selected EP(3) antagonists are also reported.

The iterative process for the discovery of a series of pyrazinone mono-amides as potent, selective and reversible non-peptide caspase-3 inhibitors (e.g., M826 and M867) is reported. These compounds display potent anti apoptotic activities in a number of cell based systems in vitro as well as in several animal models in vivo.

A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors is described. The inhibitors can be obtained after cleavage from the solid support without further purification.

Tritium labeled 2,3,4,9-tetrahydro-1H-carbazole 1a and 2a were prepared in good yields with a specific activity of 7.0 Ci/mmol (214GBq/mmol) and 4.2 Ci/mmol (155GBq/mmol), respectively. Both compounds have been synthesized in high radiochemical purity by catalytic tritium-bromine exchange of the corresponding aryl bromide precursors. The 6-bromocarbazole precursors 7 and 8 were prepared as a mixture by a three step process, involving regioselective bromination of 3c with pyridinium tribromide, oxidation of thioether 4c using m-CPBA and hydrolysis of acylsultamcarbazole 5c. Finally, HPLC separation of the enantiomers afforded the 6-bromo precursors 7 and 8 in high diastereomeric ratio (dr 99% and dr 93% respectively). Copyright 2004 John Wiley Sons, Ltd.

A method is presented for conveniently tritiating the aryl methyl sulfones of compounds identified as potent and selective inhibitors of human Cox-2 and as DP receptor antagonists. A base-catalyzed exchange reaction was conducted with deuterated water and the total deuterium incorporation, ranging from 46 to 99%, was calculated using mass spectrometry. Results from these exchanges were used as guidelines for tritium labeling giving specific radioactivities in the range of 28-120 mCi/mmol (1.03-4.43 GBq/mmol). Copyright (C) 2004 John Wiley Sons, Ltd.

The exclusive production of unsymmetrical dithioacetals in the BF3-Et2O catalyzed thioacetalization of alclehydes results from novel and unsuspected mechanistic considerations.

The amyloid-beta precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-beta (A beta) peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer's disease brains and colocalization of its APP cleavage product with A beta in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for A beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer's disease.

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A novel photoaffinity probe for the leukotriene D4 receptor (LTD4) is described. L-745310, which is structurally related to the potent LTD4 antagonist MK-0476 (Singulair), was found to selectively label a 43-kDa protein in guinea-pig lung membrane previously identified as the LTD4 receptor.

The preparation of unsymmetrical dithioacetals derived from heteroaromatic thiols and alkyl thiols is described. Insights into the rich potential of this new class of thioacetals is exemplified with the conversion to various derivatives.

A general approach to the synthesis of a new class of LTD4 antagonists is presented. The key diarylpropane framework was prepared by Claisen−Schmidt condensation and selective reduction of the enone. Depending on the bridge to the 7-chloroquinaldine moiety, alkylation or Heck coupling methodology was developed. The chiral sulfides were introduced by asymmetric reduction of the diarylpropanone intermediates and subsequent inversion of the chiral center.

Structure-activity studies leading to the discovery of a new series of non-quinoline cysLT1 receptor (LTD4 receptor) antagonists are described. These studies demonstrated that the quinoline ring system of montelukast (5) may be replaced by an appropriately substituted thienopyridine system, yielding potent compounds. Two other molecular features of montelukast, the terminal phenyl ring substitution and the vinyl link, were also reevaluated. These studies led to the identification of 1 (L-740,515), a compound with optimized in vitro and in vivo biological profiles.

Structure-activity studies leading to the discovery of 1 (MK-0476) are described. The initial compound of this series, 2, was a potent leukotriene D4 (LTD4) antagonist, but was also a peroxisomal enzyme inducer in the mouse. Structure-activity relationships around the thioether chain were explored to remove this undesirable feature. It was found that alkyl substituents in the ß position relative to the carboxylic acid reduce the potency as a peroxisomal enzyme inducer while preserving the LTD4 antagonistic properties. Dialkyl substitution essentially eliminates the enzyme induction. The optimal styryl quinoline 1 exhibited high in vitro potency and in vivo activity on oral dosing without significant liver enzyme induction in the mouse.

A new method for the synthesis of highly deuterated or tritiated leukotrienes was developed. The higher reactivity of a terminal alkene compared to a 1,2-disubstituted one permitted the selective deuteration or tritiation of the diyne 14,15, 19,19,20,20-hexadehydro LTC(4) triester 1 After hydrolysis, LTC(4) was obtained in 36% overall yield. An average of seven deuterium or tritium atoms was incorporated and the specific activity of the tritiated LTC(4) was greater than 180 Ci/mmol. 1 was obtained from the addition of glutathione to 14,15,19,19,20,20-hexadehydro LTA(4) ethyl ester which was the product of a Wittig reaction between (3,8-nonanediyn-1-yl)triphenylphosphonium iodide and 5(S), 6(S), 7(E), 9(E) ethyl 5,6-epoxy-11-oxo-7,9-undecadienoate.

The styryl quinoline thioether 5 (L-699,392) is a potent and orally active leukotriene D4 antagonist. The structure-activity studies leading to its discovery are described.

Human leukotriene C4 (LTC4) synthase was purified > 25,000-fold to homogeneity from the monocytic leukemia cell line THP-1. Beginning with taurocholate-solubilized microsomal membranes, LTC4 synthase was chromatographically resolved by (i) anion exchange, (ii) affinity chromatography (through a resin of biotinylated LTC2 immobilized on streptavidin-agarose), and then (iii) gel filtration. The final preparation contained only an 18-kDa polypeptide. The molecular mass of the pure polypeptide was consistent with an 18-kDa polypeptide from THP-1 cell membranes that was specifically photolabeled by an LTC4 photoaffinity probe, 125I-labeled azido-LTC4. On calibrated gel-filtration columns, purified LTC4 synthase activity eluted at a volume corresponding to 39.2 +/- 3.3 kDa (n = 12). The sequence of the N-terminal 35 amino acids was determined and found to be a unique sequence composed predominantly of hydrophobic amino acids and containing a consensus sequence for protein kinase C phosphorylation. We therefore conclude that human LTC4 synthase is a glutathione S-transferase composed of an 18-kDa polypeptide that is enzymatically active as a homodimer and may be phosphoregulated in vivo.

A structurally new series of potent leukotriene D4 antagonists has evolved from modification of L-695,499.

The leukotriene (LT)D4 receptor has been defined as a G-protein-coupled receptor. In order to characterize this receptor, an iodinated, photoactivatable azido derivative of LTD4 (125I-azido-LTD4) has been synthesized for use as a photoaffinity probe. The characteristics of 125I-azido-LTD4 specific binding to guinea pig lung membranes were directly comparable to those of [3H]LTD4 specific binding to this tissue. 125I-Azido-LTD4 specific binding was saturable and of high affinity, enhanced by divalent cations and inhibited by sodium ions, but not potassium ions. 125I-Azido-LTD4 specific binding was also strongly inhibited by the nonhydrolyzable GTP analog, GTP gamma S, with ATP gamma S being 100-fold less potent, suggesting this inhibition was due to selective interaction with a G-protein. The cysteinyl leukotrienes competed for 125I-azido-LTD4 specific binding to guinea pig lung membranes with the following rank order of potency: LTD4 > LTE4 > LTC4, while the non-cysteinyl LTB4 was virtually inactive. Two structurally different LTD4 receptor antagonists, MK-571 and ICI 204,219, also competed for 125I-azido-LTD4 specific binding with nanomolar potency, whereas the leukotriene synthesis inhibitor, MK-886, was 10,000-fold less active. These data are in agreement with 125I-azido-LTD4 binding specifically to a G-protein-coupled LTD4 receptor. Photolysis of 125I-azido-LTD4 under equilibrium binding conditions resulted in the selective radiolabeling of a 45-kDa guinea pig lung membrane protein. The photolabeling of this 45-kDa protein was saturable, modulated by cations and inhibited by nucleotide analogs in an analogous way to 125I-azido-LTD4 specific binding. In addition, the photolabeling of this protein was inhibited in a concentration-dependent manner by all competing ligands, with the same rank order of potency and IC50 values as determined in the 125I-azido-LTD4 binding assay. It is proposed, therefore, that this novel 45-kDa protein is the guinea pig lung LTD4 receptor.