Pseudosymmetry and bioisosterism in biaryl pyridyl competitive histamine H2-receptor antagonists.
A process of drug design has previously been described that led to the synthesis of 3-amino-5-[2-(ethylamino)-4-pyridyl]-1,2,4-triazole (4), a competitive histamine H2-receptor antagonist structurally unrelated to, but more potent than, cimetidine. A QSAR study on a subset of analogues closely related to 4 showed that gastric acid antisecretory activity increased with decreasing lipophilicity. An SAR study about 4 focused on (1) pyridine substitution compatible with both unidentate and bidentate hydrogen bonding, (2) exploration of the pseudosymmetry of 4, and (3) examination of triazole and imidazole bioisosterism. This SAR study led to a definition of the minimum structural features required for antagonist activity. The pyridylamino group is not essential for activity since replacement with a methyl group results in a decrease but not loss of activity. The triazole amino group is also not essential since replacement of the triazole amino group by methyl results in very similar activity. A triazole ring nitrogen N-1 can be replaced by a CH as in imidazole 20. The same methylimidazole in 20 when appended to a methyl pyridine as in 22 produces a competitive antagonist with Schild plot slope of unity. In summary compound 22 displays the minimum features required for antagonist activity, namely a 4-substituted pyridine appended to a 4(5)-substituted imidazole ring with single nitrogen to amidine nitrogen pair distances of 5.16 and 6.42 A.
Lipinski
C A
CA
LaMattina
J L
JL
Hohnke
L A
LA
D000818:Animals; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology*
D006635:Histamine H2 Antagonists; D007093:Imidazoles; D011725:Pyridines; D014230:Triazoles; C047233:3-amino-5-(2-(ethylamino)-4-pyridyl)-1,2,4-triazole; C047234:4-(4-(2-methylpyridyl))-2-methyl-1H-imidazole