title: Potent, orally active corticotropin-releasing factor receptor-1 antagonists containing a tricyclic pyrrolopyridine or pyrazolopyridine core.
abstract: Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC(50) = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V(D) = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, San Diego, California 92130, USA. bdyck@neurocrine.com
authors.forename: Brian
authors.initials: B
authors.lastname: Dyck
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Mustapha
authors.initials: M
authors.lastname: Haddach
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: James R
authors.initials: JR
authors.lastname: McCarthy
authors.forename: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: Collin F
authors.initials: CF
authors.lastname: Regan
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schwaebe
authors.forename: Tomas
authors.initials: T
authors.lastname: Szabo
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: Haig
authors.initials: H
authors.lastname: Bozigian
authors.forename: Ta Kung
authors.initials: TK
authors.lastname: Chen
mesh_terms: D000073:Acenaphthenes; D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010902:Pituitary Gland / Q000166:cytology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
chemical_list: C501758:1-(2-chloro-4-methylphenyl)-7-methyl-5-(1-propylbutyl)-1,3,4,5-tetrahydro-1,5,8-triazaacenaphthylene; C501759:2-(2,4-dichlorophenyl)-4-methyl-6-(1-propylbutyl)-2,6,7,8-tetrahydro-1,2,3,6-tetraazaacenaphthylene; D000073:Acenaphthenes; D006575:Heterocyclic Compounds, 3-Ring; D011720:Pyrazoles; D011725:Pyridines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP