Design and synthesis of pyridazinone-based 5-HT(2C) agonists.
The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.
Allerton
Charlotte M N
CM
Department of Discovery Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT139NJ, UK. charlotte.allerton@pfizer.com
Andrews
Mark D
MD
Blagg
Julian
J
Ellis
David
D
Evrard
Edel
E
Green
Martin P
MP
Liu
Kevin K-C
KK
McMurray
Gordon
G
Ralph
Michael
M
Sanderson
Vivienne
V
Ward
Robin
R
Watson
Lesa
L
D000818:Animals; D004285:Dogs; D015195:Drug Design; D006801:Humans; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014550:Urinary Incontinence, Stress / Q000188:drug therapy
D010879:Piperazines; D011724:Pyridazines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists