Design and synthesis of novel pyrrolidine-containing bradykinin antagonists.
The design and synthesis of novel pyrrolidine-containing bradykinin antagonists, II, are described. Conformational analysis suggested that a pyrrolidine moiety could substitute for the N-methyl cis-amide moiety of FR 173657. The in vitro binding data showed that the (S)-isomer of II was potent in the bradykinin B(2) receptor-binding assay with a K(i) of 33 nM. The opposite isomer, (R)-II, had a K(i) of 46 nM. The in vitro binding data confirmed our conformational hypothesis.
Lee
Jung
J
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, PO Box 776, Spring House, PA 19477-0776, USA. jlee@prdus.jnj.com
Reynolds
Charles
C
Jetter
Michele C
MC
Youngman
Mark A
MA
Hlasta
Dennis J
DJ
Dax
Scott L
SL
Stone
Dennis J
DJ
Zhang
Sui-Po
SP
Codd
Ellen E
EE
D001920:Bradykinin / Q000037:antagonists & inhibitors*; D015195:Drug Design; D007536:Isomerism; D008958:Models, Molecular; D008968:Molecular Conformation; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018002:Receptors, Bradykinin / Q000378:metabolism
D011759:Pyrrolidines; D018002:Receptors, Bradykinin; D001920:Bradykinin