Potent, orally active corticotropin-releasing factor receptor-1 antagonists containing a tricyclic pyrrolopyridine or pyrazolopyridine core.
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.
Dyck
Brian
B
Department of Medicinal Chemistry, Neurocrine Biosciences, San Diego, California 92130, USA. bdyck@neurocrine.com
Grigoriadis
Dimitri E
DE
Gross
Raymond S
RS
Guo
Zhiqiang
Z
Haddach
Mustapha
M
Marinkovic
Dragan
D
McCarthy
James R
JR
Moorjani
Manisha
M
Regan
Collin F
CF
Saunders
John
J
Schwaebe
Michael K
MK
Szabo
Tomas
T
Williams
John P
JP
Zhang
Xiaohu
X
Bozigian
Haig
H
Chen
Ta Kung
TK
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
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