Novel angiotensin II receptor antagonists. Design, synthesis, and in vitro evaluation of dibenzo[a,d]cycloheptene and dibenzo[b,f]oxepin derivatives. Searching for bioisosteres of biphenylyltetrazole using a three-dimensional search technique.
Three-dimensional substructure searching (3D search), using the program MACCS-3D, was utilized for designing novel angiotensin II receptor antagonists which contain a bioisostere of the biphenylyltetrazole moiety of DuP 753. A 3D query was prepared from an overlay model of substructures of several potent AII antagonists. The search system retrieved 139 compounds from the database MDDR-3D, which consisted of 29,400 medicinal patent compounds. A tricyclic compound was selected from the retrieved compounds and then evolved by considering steric fitness to the overlay model and synthetic feasibility. Finally, various novel AII antagonists having dibenzo[a,d]cycloheptene or dibenzo[b,f]oxepin were designed and synthesized. The receptor binding activity (Ki) for several members of this series was in the 10(-10) M range, demonstrating the ability of 3D search technique to explore new lead structures.
Kiyama
R
R
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Honma
T
T
Hayashi
K
K
Ogawa
M
M
Hara
M
M
Fujimoto
M
M
Fujishita
T
T
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D002460:Cell Line; D003986:Dibenzocycloheptenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003990:Dibenzoxepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007256:Information Systems; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000737:chemistry*
D057911:Angiotensin Receptor Antagonists; D003986:Dibenzocycloheptenes; D003990:Dibenzoxepins; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II