Synthesis and evaluation of pyridone-phenoxypropyl-R-2-methylpyrrolidine analogues as histamine H3 receptor antagonists.
6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]-phenyl}-2H-pyridazin-3-one 6 (Irdabisant; CEP-26401) was recently reported as a potent H(3)R antagonist with excellent drug-like properties and in vivo activity that advanced into clinical evaluation. A series of pyridone analogs of 6 was synthesized and evaluated as H(3)R antagonists. Structure-activity relationships revealed that the 5-pyridone regiomer was optimal for H(3)R affinity. N-Methyl 9b showed excellent H(3)R affinity, acceptable pharmacokinetics and pharmaceutical properties. In vivo evaluation of 9b showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG model.
Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. nbecknell@cephalon.com
Nadine C
NC
Becknell
Jacquelyn A
JA
Lyons
Lisa D
LD
Aimone
John A
JA
Gruner
Joanne R
JR
Mathiasen
Rita
R
Raddatz
Robert L
RL
Hudkins
D000818:Animals; D004195:Disease Models, Animal; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D054828:Histamine H3 Antagonists; D011724:Pyridazines; D011759:Pyrrolidines; C561238:6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one