title: Discovery of pyrrolo[2,3-d]pyrimidin-4-ones as corticotropin-releasing factor 1 receptor antagonists with a carbonyl-based hydrogen bonding acceptor.
abstract: A new class of pyrrolo[2,3-d]pyrimidin-4-one corticotropin-releasing factor 1 (CRF(1)) receptor antagonists has been designed and synthesized. In general, reported CRF(1) receptor antagonists possess a sp(2)-nitrogen atom as hydrogen bonding acceptor (HBA) on their core scaffolds. We proposed to use a carbonyl group of pyrrolo[2,3-d]pyrimidin-4-one derivatives as a replacement for the sp(2)-nitrogen atom as HBA in classical CRF(1) receptor antagonists. As a result, several pyrrolo[2,3-d]pyrimidin-4-one derivatives showed CRF(1) receptor binding affinity with IC(50) values in the submicromolar range. Ex vivo (125)I-sauvagine binding studies showed that 2-(dipropylamino)-3,7-dimethyl-5-(2,4,6-trimethylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (16b) (30 mg/kg, p.o.) was able to penetrate into the brain and inhibit radioligand binding to CRF(1) receptors (frontal cortex, olfactory bulb, and pituitary) in mice. We identified pyrrolo[2,3-d]pyrimidin-4-one derivatives as the first CRF(1) antagonists with a carbonyl-based HBA.
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Aso_Kazuyoshi@takeda.co.jp
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Aso
authors.forename: Katsumi
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Michiyo
authors.initials: M
authors.lastname: Mochizuki
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Yuu
authors.initials: Y
authors.lastname: Sako
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yano
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006860:Hydrogen Bonding; D007659:Ketones / Q000737:chemistry; D051379:Mice; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D007659:Ketones; D011743:Pyrimidines; D011758:Pyrroles; C450639:Pyrrolo(2,3-d)pyrimidine; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1