Dihydropyridopyrazinones and dihydropteridinones as corticotropin-releasing factor-1 receptor antagonists: structure-activity relationships and computational modeling.
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.
Dzierba
Carolyn D
CD
Discovery Chemistry, Neuroscience Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
Tebben
Andrew J
AJ
Wilde
Richard G
RG
Takvorian
Amy G
AG
Rafalski
Maria
M
Kasireddy-Polam
Padmaja
P
Klaczkiewicz
John D
JD
Pechulis
Anthony D
AD
Davis
Amy L
AL
Sweet
Mark P
MP
Woo
Alex M
AM
Yang
Zhicai
Z
Ebeltoft
Sarah M
SM
Molski
Thaddeus F
TF
Zhang
Ge
G
Zaczek
Robert C
RC
Trainor
George L
GL
Combs
Andrew P
AP
Gilligan
Paul J
PJ
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
C101531:CRF receptor type 2; D011621:Pteridines; D011724:Pyridazines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1