Bradykinin B1 receptor antagonists: an alpha-hydroxy amide with an improved metabolism profile.
A series of carbo- and heterocyclic alpha-hydroxy amide-derived bradykinin B1 antagonists was prepared and evaluated. A 4,4-difluorocyclohexyl alpha-hydroxy amide was incorporated along with a 2-methyl tetrazole in lieu of an oxadiazole to afford a suitable compound with good pharmacokinetic properties, CNS penetration, and clearance by multiple metabolic pathways.
Kuduk
Scott D
SD
Department of Medicinal Chemistry, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. scott_d_kuduk@merck.com
Chang
Ronald K
RK
Dipardo
Robert M
RM
Di Marco
Christina N
CN
Murphy
Kathy L
KL
Ransom
Richard W
RW
Reiss
Duane R
DR
Tang
Cuyue
C
Prueksaritanont
Thomayant
T
Pettibone
Douglas J
DJ
Bock
Mark G
MG
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists; D002490:Central Nervous System / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D000577:Amides; D065169:Bradykinin B1 Receptor Antagonists; D013777:Tetrazoles