Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists.
Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
Stocking
Emily M
EM
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
Aluisio
Leah
L
Atack
John R
JR
Bonaventure
Pascal
P
Carruthers
Nicholas I
NI
Dugovic
Christine
C
Everson
Anita
A
Fraser
Ian
I
Jiang
Xiaohui
X
Leung
Perry
P
Lord
Brian
B
Ly
Kiev S
KS
Morton
Kirsten L
KL
Nepomuceno
Diane
D
Shah
Chandravadan R
CR
Shelton
Jonathan
J
Soyode-Johnson
Akinola
A
Letavic
Michael A
MA
D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
C550998:1-(2-(4-cyclobutyl-(1,4)diazepane-1-carbonyl)-4-(3-fluorophenoxy)pyrrolidin-1-yl)ethanone; D001381:Azepines; D054828:Histamine H3 Antagonists; D011759:Pyrrolidines; D018100:Receptors, Histamine H3