title: Dihydropyridopyrazinones and dihydropteridinones as corticotropin-releasing factor-1 receptor antagonists: structure-activity relationships and computational modeling.
abstract: The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.
authors.affiliation: Discovery Chemistry, Neuroscience Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Dzierba
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.forename: Richard G
authors.initials: RG
authors.lastname: Wilde
authors.forename: Amy G
authors.initials: AG
authors.lastname: Takvorian
authors.forename: Maria
authors.initials: M
authors.lastname: Rafalski
authors.forename: Padmaja
authors.initials: P
authors.lastname: Kasireddy-Polam
authors.forename: John D
authors.initials: JD
authors.lastname: Klaczkiewicz
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Pechulis
authors.forename: Amy L
authors.initials: AL
authors.lastname: Davis
authors.forename: Mark P
authors.initials: MP
authors.lastname: Sweet
authors.forename: Alex M
authors.initials: AM
authors.lastname: Woo
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Yang
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Ebeltoft
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Robert C
authors.initials: RC
authors.lastname: Zaczek
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gilligan
mesh_terms: D000818:Animals; D002831:Choroid Plexus / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D066298:In Vitro Techniques; D008958:Models, Molecular; D011621:Pteridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013552:Swine; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D011621:Pteridines; D011724:Pyridazines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1