Design and synthesis of pyrido[2,3-d]pyrimidine derivatives for a novel PAC1 receptor antagonist.
Basic Information
ID: ALA5131488
Journal: Eur J Med Chem
Title: Design and synthesis of pyrido[2,3-d]pyrimidine derivatives for a novel PAC1 receptor antagonist.
Authors: Takasaki I, Watanabe A, Okada T, Kanayama D, Nagashima R, Shudo M, Shimodaira A, Nunomura K, Lin B, Watanabe Y, Gouda H, Miyata A, Kurihara T, Toyooka N.
Abstract: Since PA-8 (5-(4-(Allyloxy)-3-methoxyphenyl)-2-amino-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) was recently identified as a novel small-molecule antagonist of the pituitary adenylate cyclase-activating polypeptide (PACAP) type I (PAC1) receptor, a series of pyrido[2,3-d]pyrimidine derivatives have been designed, synthesized and subsequently evaluated for antagonistic activity on the PAC1 receptor. In this study, we synthesized 21 derivatives based on the PA-8 structure. Among them, the compound 2o (2-Amino-5-(3-trifluoromethoxy-phenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) showed more potent antagonistic activities than PA-8. Intrathecal (i.t.) injection of 2o blocked the induction of PACAP-induced aversive behaviors and mechanical allodynia in mice, and the effects were more potent than those of PA-8. A single i.t. injection of 2o also inhibited spinal nerve ligation (SNL)-induced mechanical allodynia. Repeated intraperitoneal administration of 2o gradually reduced the SNL-induced mechanical allodynia, and this effect appeared earlier than for PA-8. In addition, 2o exhibited a favorable ADME and pharmacokinetics profiles. These results suggest that 2o may become an analgesic for the treatment of neuropathic pain.
CiteXplore: 35124531
DOI: 10.1016/j.ejmech.2022.114160
Patent ID: ┄