- Substituted biphenyl derivatives
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A compound of the following structure: STR1 wherein, when R8 =H: R1 =alkyl, cycloalkyl, arylalkyl, aryl; R2 =cycloalkyl, aryl, C3 -C10 alkyl; X,Y=O, S(O)n, NH; Z=CHO, CO2 R3
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- Substituted biphenyl derivatives
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A compound of the following structure: STR1 wherein R8 =H: R1 =alkyl, cycloalkyl, arylalkyl, aryl; R2 =cycloalkyl, aryl, C3 -C10 alkyl; X,Y=O, S(O)n, NH; Z=CO2 R3, C(O
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- Biarylcarboxylic acids and -amides: Inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behavior in the ferret
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In addition to having desirable inhibitory effects on inflammation, anaphylaxis, and smooth muscle contraction, PDE-IV inhibitors also produce undesirable side effects including nausea and vomiting. In general, compounds that inhibit PDE-IV also potently displace [3H]rolipram from a high-affinity binding site in rat cortex. While this binding site has not been identified, it has been proposed to be an allosteric binding site on the PDE-IV enzyme. Preliminary studies have suggested that the emetic potency of PDE-IV inhibitors is correlated with affinity for the brain rolipram binding site rather than potency at inhibiting PDE-IV enzyme activity. Efforts to eliminate the emetic potential of PDE-IV inhibitors were directed toward developing compounds with decreased [3H]rolipram binding affinity while retaining PDE-IV potency. Thus, a novel series of 4-(3-alkoxy-4- methoxyphenyl)benzoic acids and their corresponding carboxamides were prepared and evaluated for their PDE-IV inhibitory and rolipram binding site properties. Modification of the catechol ether moiety led to phenylbutoxy and phenylpentoxy analogues that provided the desired activity profile. Specifically, 4-[3-(5-phenylpentoxy)-4-methoxyphenyl]-2-methylbenzoic acid, 18, was found to exhibit potent PDE-IV inhibitory activity (IC50 0.41 μM) and possessed 400 times weaker activity than rolipram for the [3H]rolipram binding site. In vivo, compound 18 was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 8.8 mg/kg, po) and demonstrated a significant reduction in emetic side effects (ferret, 20% emesis at 30 mg/kg, po).
- Duplantier, Allen J.,Biggers, Michael S.,Chambers, Robert J.,Cheng, John B.,Cooper, Kelvin,Damon, David B.,Eggler, James F.,Kraus, Kenneth G.,Marfat, Anthony,Masamune, Hiroko,Pillar, Joann S.,Shirley, John T.,Umland, John P.,Watson, John W.
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p. 120 - 125
(2007/10/03)
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- TRI-SUBSTITUTED PHENYL DERIVATIVES AND THEIR USE IN PHARMACEUTICAL COMPOSITIONS AND METHODS OF TREATMENT
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Compounds of formula (1) are described wherein Y represents a halogen atom or a group -OR1 , where R1 is an optionally substituted alkyl group; R2 represents an optionally substituted cycloalkyl or cycloalkenyl group; R3 is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen or sulphur atoms or a group-N(R4)- where R4 is a hydrogen atom or an alkyl group; X is -O-, -S-, or -N(R5)-, where R5 is a hydrogen or an alkyl group; with the proviso that when X is -O-then R3 is not a 3-cyanamino-6-pyridazinyl or a 3-chloro-6-pyridazinyl group; and the salts, solvates, hydrates and N-oxides thereof, The compounds are selective and potent inhibitors of phosphodiesterase IV and are useful for the prophylaxis and treatment of inflammatory diseases and the alleviation of conditions associated with central nervous malfunction
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