Structure-activity studies of pyridinylalkyl-isocytosine H1-receptor antihistamines and identification of an active conformation.
For a series of 2-(pyridin-2-ylbutylamino)-5-(3-picolinylmethyl)pyrimidin- 4(1H)-ones (isocytosines) substituted in the pyridine 3-position, activity as H1- and H2-receptor histamine antagonists appears to correlate with the size of the 3-substituent. Steric interaction between the substituent and the butyl chain is explored by conformational analysis using Molecular Mechanics and Molecular Orbital calculations on 2-propyl- and 2-propyl-3-methyl-pyridines; it appears that the substituent may alter activity by changing the preferred conformation of the drug. This observation is extended by synthesis of a semirigid bicyclic analogue wherein 3-methylpyridinylbutyl is replaced by tetrahydroquinolinylpropyl. This compound is 2-3 times more potent as an H1-receptor antagonist confirming that a trans/trans conformation favours activity. Although derived from an H2-antagonist structure, the compound is not an antagonist at histamine H2 receptors thus proving that the conformational requirements are different at H1 and H2 receptors.
Smithkline Beecham Research, Hertfordshire England.
D G
DG
Cooper
G J
GJ
Durant
C R
CR
Ganellin
R J
RJ
Ife
M L
ML
Meeson
G S
GS
Sach
D000758:Anesthesia; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D003596:Cytosine / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
D006635:Histamine H2 Antagonists; D003596:Cytosine