Potent inhibitors of the MAP kinase p38.

The MAP kinase p38 plays a key role in the biosynthesis of the inflammatory cytokines TNF-alpha and IL-1. We have developed a novel series of potent p38 inhibitors that could lead to new methods of treatment for inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.

The development of novel and selective p56lck tyrosine kinase inhibitors.

Early T-cell receptor mediated signal transduction involves the activation of several tyrosine protein kinases. One of these tyrosine kinases, p56lck, is expressed primarily in T-cells and Natural Killer (NK) cells and has been shown to be critical for their proliferative and effector functions. Indandiones have been identified as a potent and selective chemical class that inhibits p56lck.

Design and discovery of RWJ 22108--a novel bronchoselective calcium channel blocker.

A series of cyclic sulfone dihydropyridines ranging in sulfone ring size from five to nine membered have been evaluated for calcium antagonist activity. Increasing the sulfone ring size from 5 to 8 membered resulted in a two orders of magnitude in vitro potency increase. Aromatic substitution which favored tracheal effects over aortic effects was found to be 2-NO2 and 2-Cl, 6-F. The ester side chain which was found to maximize in vivo activity was the N-benzyl-N-methyl aminoethyl moiety. Combination of all these structural features resulted in RWJ 22108, a bronchoselective calcium channel blocker which preclinically exhibits an antiasthmatic profile.

Experimental antiasthmatic activity of RWJ 22108: a bronchoselective calcium entry blocker.

RWJ 22108 (N-benzyl-N-methylaminoethyl 9-(2-chloro-6-fluorophenyl)-2,3,4,5,6,9-hexahydro-7-methyl-1, 1-dioxothiacyclohepteno-[3,2-b]pyridine-8-carboxylate) is a new bronchoselective calcium entry blocker with potential use as an antiasthmatic agent. Previous studies have shown that RWJ 22108 is a potent calcium entry blocker in vitro and demonstrates tissue selectivity for airway smooth muscle over vascular smooth muscle. The current study demonstrates the in vivo activity of RWJ 22108 in several different models of airway obstruction and asthma. RWJ 22108 relaxes preconstricted airways in dogs with little effect on blood pressure when administered by aerosol. In addition, it inhibits airway obstruction induced by antigen, histamine and exogenous leukotriene D4 in guinea pigs. In a conscious sheep model of allergic asthma, aerosol RWJ 22108 inhibits antigen-induced early and late phase airway obstruction and also the cellular infiltration associated with late phase. Total leukotrienes production is decreased in the guinea pig model probably as a result of fewer inflammatory cells infiltrating the lungs as shown in the sheep model of late phase. These data suggest that RWJ 22108 may have pharmacological potential in the clinical management of asthma.

Structure-activity relationships for enhancement of adenosine A1 receptor binding by 2-amino-3-benzoylthiophenes.

The structural requirements for stimulation of adenosine A1 agonist binding by 2-amino-3-benzoylthiophenes and related compounds were investigated. Slowing of the dissociation of [3H]N6cyclohexyladenosine binding was used as a specific measure of the allosteric effects of these compounds. The thiophene ring could be replaced with benzene but not with several nitrogen-containing heterocycles. The 2-amino group was required, and at least one hydrogen on the amino group appeared to be necessary for activity. The keto carbonyl was also essential. Alkyl substitution at the 4-position of the thiophene ring increased activity, whereas 5-position substitution appeared to have little effect. Activity was also increased by various substitutions on the phenyl ring, with 3-(trifluoromethyl) showing optimal activity. The phenyl ring could be replaced with cyclohexyl without major loss of activity. 1-Aminofluoren-9-one, a conformationally locked derivative, was active. Based in part in the latter observation, the active conformation is proposed to have an intramolecular hydrogen bond between the amino nitrogen and the carbonyl oxygen. Because the 2-amino-3-benzoylthiophenes showed competitive adenosine antagonism as well as allosteric enhancement, their affinities as competitive inhibitors of [3H]8-cyclopentyl-1,3-dipropylxanthine binding to A1 receptors were also assessed. Structure-activity relationships for competitive antagonism were distinct from those for allosteric enhancement, with ratios between the two activities varying by more than 1000-fold. Of the analogs tested, (2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone (PD 81,723) had the most favorable ratio of enhancement to antagonism.

Personnel selection--4. Conclusion.

This article, the last in a series of four, discusses general conclusions on selection methods. Earlier articles examined the principles of systematic selection, the use of psychological tests and the selection interview.

Personnel selection - 3. Interviewing.

This article, the third in a series of four, examines the selection interview. The selection procedure and the use of psychological tests were discussed in earlier articles. General conclusions will be discussed in the final article.

Personnel selection--2. Testing.

This article, the second in a series of four, examines the use of psychological tests within the selection procedure. The first article examined the principles of systematic selection. Later articles will discuss selection interviewing and general conclusions on selection methods.