George B. Mullen

2-(Substituted amino)-2-[2′-hydroxy-2′-alkyl(or aryl)]ethyltricyclo-[3.3.1.13,7]decane derivatives: a novel class of anti-hypoxia agents

Abstract The synthesis and biological activity of a series of 2-(substituted amino)-2-[2′-hydroxy-2′-alkyl(or aryl)]-ethyltricyclo[3.3.1.13,7] decane derivatives 17, are described. Compounds 17 represent a novel class of anti-hypoxia agents. In addition, they were found to exert anti-parkinson, anti-convulsant and analgesic activities. The degree of anti-hypoxia activity was shown to be dependent upon the length of the carbon side chain: the two most active compounds were the 2′-hexadecyl 17e and 2′-tetradecyl 17f analogs. The presence of an adamantyl ring and an alkyl side chain in the molecule of aminoalcohols 17 may have facilitated their penetration through the blood-brain barrier.The synthesis and biological activity of a series of 2-(substituted amino)-2-[2′-hydroxy-2′-alkyl(or aryl)]-ethyltricyclo[3.3.1.13,7] decane derivatives 17, are described. Compounds 17 represent a novel class of anti-hypoxia agents. In addition, they were found to exert anti-parkinson, anti-convulsant and analgesic activities. The degree of anti-hypoxia activity was shown to be dependent upon the length of the carbon side chain: the two most active compounds were the 2′-hexadecyl 17e and 2′-tetradecyl 17f analogs. The presence of an adamantyl ring and an alkyl side chain in the molecule of aminoalcohols 17 may have facilitated their penetration through the blood-brain barrier.

Synthesis and biological activity of enantiomers of a conformationally restricted muscarone analog

Abstract A short and efficient synthesis of both enantiomers of 2,8-dimethyl-1-oxa-8-azaspiro[4.5]-decan-3-one is described. The biological activity of the racemate resides predominantly in the S-enantiomer. While the S-isomer is a full M2-agonist, the R-isomer is devoid of M2 efficacy.

Development of a pharmacological target profile for muscarinic agonists

The purpose of these studies was to determine the levels of intrinsic activity in vitro at muscarinic receptor pharmacological subtypes (M1, M2, and M3) that would optimize cognitive activity while minimizing acute adverse cholinergic effects in vivo. These levels of intrinsic efficacy at M1, M2, and M3 receptor subtypes, the target profile, could then be used to assess novel compounds for antidementia potential. To accomplish this, a series of muscarinic agonists (spirofuranone analogues) was prepared, and compounds with variable intrinsic activity at M1, M2, and M3 receptor subtypes were selected for characterization in a series of in vivo tests (reversal of scopolamine‐induced memory impairment, and agonist‐induced salivation, lacrimation, diarrhea, hypothermia, and bradycardia). Memory enhancement was found to correspond best to M1 activity with an apparent threshold of intrinsic activity of approximately 50% in human M1‐transfected CHO cells. Surprisingly, a preferential M3 agonist (ARL 16037) produced a partial reversal of scopolamine‐induced memory impairment, but only at high doses that resulted in severe diarrhea. However, it was unclear whether this memory effect was due to the weak M1 or strong M3 agonist activity of this compound. Three muscarinic agonists (ARL 14995, ARL 15467, and ARL 15424) reversed the scopolamine‐induced memory deficits, as well as the cholinesterase inhibitor tacrine, suggesting that muscarinic agonists may be at least as clinically effective as cholinesterase inhibitors. Acute cholinergic side effects (diarrhea, salivation, lacrimation) corresponded best to M3 activity (contraction of guinea pig trachea) and were greatly diminished with in vitro intrinsic M3 activity of 50% or less. Agonist‐induced heart rate reduction corresponded best to M2 receptor efficacy (inhibition of rat heart adenylyl cyclase). Identification of compounds without detectable in vitro intrinsic activity but with measurable heart rate effects suggested that signal amplification at M2 receptors in vitro limited detection of weak partial agonists. Development of the target profile has proven useful in rapid evaluation of compounds for optimization of muscarinic pharmacological properties. Drug Dev. Res. 40:117–132, 1997.

Studies on Antifungal Agents

The influence of the C-5-aromatic substitution on the in vitro antifungal activity of novel ci5–3,5-substituted isoxazolidine derivatives was investigated. Compounds having a C-5-(substituted phenoxy)

In vitro antifungal activity of novel substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine derivatives.

To further investigate the role of the C-5 substituent on the isoxazolidine ring on antifungal activity, a number of novel substituted 3,5-diphenyl-3-( lH-imidazol1 -ylmethyl)-2-methylisoxazoiidine derivatives (1) were prepared and assayed in vitro using broth and agar cultures. The synthesis of the title compounds involved a 1,3-dipolar cycloaddition reaction of substituted phenyl1H-imidazol1-ylmethyl nitrones with appropriate styrene precursors. The resulting cis/trans mixtures of the corresponding isoxazolidines were separated by flash chromatography on silica gel (TABLE 1):

Comparisons of ketoconazole, PR 969-566, PR 967-234, and PR 967-248 as antifungals in vitro and in the rat model of candidal vaginitis based on efficacy/safety profiles.

Critical factors in the rational development of new antifungal drugs are standardized, quantitative, and coordinated approaches involving chemical discovery, preclinical evaluations, and comparisons of novel antifungal candidates with positive reference compounds. The reference compound ketoconazole has been found to be effective clinically against vaginal candidiasis as well as in the rat model of candidal vaginitis. A new chemical series of isoxazolidine compounds was targeted for preclinical evaluations involving 1) in vitro testing; 2 ) in vivo analysis in the rat model of candidal vaginitis; and 3 ) safety considerations involving hormonal, central nervous system (CNS), and cardiovascular (CV) effects. The following antifungal candidates were first compared to ketoconazole for in vitro activity: 1) PR 969-566 or cis-3-(4-chlorophenyl) 3 [ ( 1Himidazol1 yl) methyl] 2 -methyl 5 { [ ( 4 methylphenyl) thiolmethyl) isoxazolidine; 2) PR 967-234 or cis-3,5-bis(4-chlorophenyl)-3-[ ( ltl-imidazoll-yl)methyl]-2-methylisoxazolidine; and 3) PR 967-248 or cis-5-[ (4-chlorophenoxy ) methy1]-3-(4-~hlorophenyl)-3-[( lH-imidazol1 -yl)methyl]-2-methylisoxazolidine. In the in vitro evaluations, minimum inhibitory concentration (MIC) values were used for comparing antifungal activity of all four compounds against two strains of Candida