ChemInform Abstract: Benzo‐ and Pyrido‐1,4‐oxazepin‐5‐ones and ‐thiones: Synthesis and Structure‐Activity Relationships of a New Series of H1 Antihistamines.

Cale, Albert D.; Gero, Thomas W.; Walker, K. R.; Lo, Young S.; Welstead, William J.; Jaques, Larry W.; Johnson, Ashby F.; Leonard, Charles A.; Nolan, Joseph C.; Johnson, D.

doi:10.1002/chin.199008195

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“…In the rocastine series, the greater potency of the pyridyl compounds relative to their phenyl analogues suggests that the pyridyl compounds relative to their phenyl analogues suggests that the pyridyl ring of 1 may fit the same receptor site as the pyridine ring in 31, while the increase in potency on introduction of a chloro substituent at the 7-position of 1 (analogue 2) parallels the SAR associated with the chlorphenyl group of 31, sug- gesting a similar receptor fit for the pyridine ring of 1 and the chlorophenyl group of 31. Super imposition of the binding conformation of the active R isomer of the chlorinated analogue (2) of rocastine over the S isomer of chlorpheniramine (31) in Figure 8 supports the latter interpretation and shows that the chloro substituent of each is, in fact, simlarly positioned.…”

Section: Discussionmentioning

confidence: 55%

Optical isomers of rocastine and close analogs: synthesis and H1 antihistaminic activity of its enantiomers and their structural relationship to the classical antihistamines

Sleevi

Cale²,

Gero³

et al. 1991

J. Med. Chem.

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The enantiomers of 2-[2-(dimethylamino)ethyl]-3,4-dihydro-4-methylpyrido[3,2-f]-1,4- oxazapine-5(2H)-thione (rocastine) and two of its more potent analogues were prepared with an enantiomeric purity of greater than 99.9%. The antihistaminic activity of these compounds was assessed by their ability to block histamine-induced lethality in guinea pigs and to inhibit [3H]mepyramine binding to guinea pig cortex. In this series, compounds having the R configuration at the 2-position are at least 300 times more potent than the S isomers. Conformational analysis and molecular modeling suggest that rocastine can adopt a conformation in which the pyridine ring, ether oxygen, and protonated amine functions are positioned similarly to the corresponding elements of the probable binding conformers of some of the more classical antihistamines. This conformation, boatlike in the oxazepine ring with the side chain quasi-equatorial and folded back toward the ring, is the likely binding conformer at the histamine H1 receptor, and the available structure-activity relationship data is consistent with this interpretation.

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Section: Discussionmentioning

confidence: 55%

Optical isomers of rocastine and close analogs: synthesis and H1 antihistaminic activity of its enantiomers and their structural relationship to the classical antihistamines

Sleevi

Cale²,

Gero³

et al. 1991

J. Med. Chem.

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show abstract

ChemInform Abstract: Benzo‐ and Pyrido‐1,4‐oxazepin‐5‐ones and ‐thiones: Synthesis and Structure‐Activity Relationships of a New Series of H1 Antihistamines.

Abstract: A series of benzo‐ or pyrido‐1,4‐oxazepinones and the corresponding ‐thiones such as the compounds (VIII) and (XI) is prepared.

Cited by 1 publication

References 1 publication

Optical isomers of rocastine and close analogs: synthesis and H1 antihistaminic activity of its enantiomers and their structural relationship to the classical antihistamines

Optical isomers of rocastine and close analogs: synthesis and H1 antihistaminic activity of its enantiomers and their structural relationship to the classical antihistamines

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