title: Synthesis and pharmacological evaluation of aminopyrimidine series of 5-HT1A partial agonists.
abstract: Aminopyrimidine 2 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine) emerged from a high throughput screen as a novel 5-HT(1A) agonist. This compound showed moderate potency for 5-HT(1A) in binding and functional assays, as well as moderate metabolic stability. Implementation of a strategy for improving metabolic stability by lowering the lipophilicity (cLogD) led to identification of methyl ether 31 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-(2-methoxyethyl)pyrimidin-2-amine) as a substantially improved compound within the series.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, United States. Amy.Dounay@pfizer.com
authors.forename: Amy B
authors.initials: AB
authors.lastname: Dounay
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Barta
authors.forename: Jack A
authors.initials: JA
authors.lastname: Bikker
authors.forename: Susan A
authors.initials: SA
authors.lastname: Borosky
authors.forename: Brian M
authors.initials: BM
authors.lastname: Campbell
authors.forename: Terry
authors.initials: T
authors.lastname: Crawford
authors.forename: Lynne
authors.initials: L
authors.lastname: Denny
authors.forename: Lori M
authors.initials: LM
authors.lastname: Evans
authors.forename: David L
authors.initials: DL
authors.lastname: Gray
authors.forename: Pil
authors.initials: P
authors.lastname: Lee
authors.forename: Edward A
authors.initials: EA
authors.lastname: Lenoir
authors.forename: Wenjian
authors.initials: W
authors.lastname: Xu
mesh_terms: D002065:Buspirone / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C538881:4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-(2-methoxyethyl)pyrimidin-2-amine; C538879:4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine; D007211:Indoles; D011743:Pyrimidines; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D002065:Buspirone