title: Design and synthesis of pyridazinone-based 5-HT(2C) agonists.
abstract: 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.
authors.affiliation: Department of Discovery Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT139NJ, UK. charlotte.allerton@pfizer.com
authors.forename: Charlotte M N
authors.initials: CM
authors.lastname: Allerton
authors.forename: Mark D
authors.initials: MD
authors.lastname: Andrews
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
authors.forename: David
authors.initials: D
authors.lastname: Ellis
authors.forename: Edel
authors.initials: E
authors.lastname: Evrard
authors.forename: Martin P
authors.initials: MP
authors.lastname: Green
authors.forename: Kevin K-C
authors.initials: KK
authors.lastname: Liu
authors.forename: Gordon
authors.initials: G
authors.lastname: McMurray
authors.forename: Michael
authors.initials: M
authors.lastname: Ralph
authors.forename: Vivienne
authors.initials: V
authors.lastname: Sanderson
authors.forename: Robin
authors.initials: R
authors.lastname: Ward
authors.forename: Lesa
authors.initials: L
authors.lastname: Watson
mesh_terms: 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
chemical_list: 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