Potent, Orally Active Corticotropin-Releasing Factor Receptor-1 Antagonists Containing a Tricyclic Pyrrolopyridine or Pyrazolopyridine Core

• Published in: Journal of medicinal chemistry Vol. 48; no. 12; pp. 4100 - 4110
• Main Authors: Dyck, Brian, Grigoriadis, Dimitri E, Gross, Raymond S, Guo, Zhiqiang, Haddach, Mustapha, Marinkovic, Dragan, McCarthy, James R, Moorjani, Manisha, Regan, Collin F, Saunders, John, Schwaebe, Michael K, Szabo, Tomas, Williams, John P, Zhang, Xiaohu, Bozigian, Haig, Chen, Ta Kung
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.06.2005; Amer Chemical Soc
• Subjects: Acenaphthenes; Adrenocorticotropic Hormone - antagonists & inhibitors; Animals; Biological and medical sciences; Biological Availability; Blood-Brain Barrier - metabolism; Cells, Cultured; Chemistry, Medicinal; Cyclic AMP - biosynthesis; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - pharmacokinetics; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pituitary Gland - cytology; Pyrazoles - chemical synthesis; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Pyridines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - pharmacokinetics; Pyrroles - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors; Receptors, Corticotropin-Releasing Hormone - metabolism; Science & Technology; Stress, Psychological - metabolism; Structure-Activity Relationship; DESIGN; HORMONE; DEPRESSED-PATIENTS; ANXIETY; R121919; MAJOR DEPRESSION; BINDING; CRF1 RECEPTOR; Peptide hormone; Central nervous system; Blood brain barrier; Dose activity relation; Absorption; Structure activity relation; Chlorine Organic compounds; Antagonist; Chemical synthesis; Release; CRF1 receptor; Rodentia; Elimination; Oral administration; Tricyclic compound; In vitro; In vivo; Vertebrata; Mammalia; Adrenocorticotropic hormone; Penetration; Adenohypophyseal hormone; Mouse; Animal; Distribution; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050070m

Two new classes of tricyclic-based corticotropin-releasing factor (CRF1) 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 CRF1 receptor (K i = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC50 = 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.