title: Discovery of NBI-77860/GSK561679, a potent corticotropin-releasing factor (CRF1) receptor antagonist with improved pharmacokinetic properties.
abstract: Antagonists of the corticotropin-releasing factor (CRF) neuropeptide may prove effective in treating stress and anxiety related disorders. In an effort to identify antagonists with improved physico-chemical properties a new series of CRF(1) antagonists were designed to substitute the propyl groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core of 1 with heterocycles. Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, San Diego, CA 92130, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Tellew
authors.forename: Marion
authors.initials: M
authors.lastname: Lanier
authors.forename: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: Emily
authors.initials: E
authors.lastname: Lin
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Luo
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Slee
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: Sam R J
authors.initials: SR
authors.lastname: Hoare
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
authors.forename: Yves
authors.initials: Y
authors.lastname: St Denis
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Enza
authors.initials: E
authors.lastname: Di Modugno
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
mesh_terms: D053961:Azabicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D053961:Azabicyclo Compounds; C556497:NBI 77860; D010069:Oxadiazoles; D011720:Pyrazoles; D011725:Pyridines; D018019:Receptors, Corticotropin-Releasing Hormone; D011994:Recombinant Proteins; C118531:pyrazolopyridine