Synthesis and structure–activity relationships of 8-substituted-2-aryl-5-alkylaminoquinolines: Potent, orally active corticotropin-releasing factor-1 receptor antagonists
Introduction
Corticotropin releasing factor (CRF), isolated by Vale et al. in 1981 as a 41 amino acid peptide, is the primary regulator of hypothalamic-pituitary-adrenal (HPA) stress response.1 It is known that CRF exerts its biological functions through binding to two GPCR subfamily receptors, the CRF1 and CRF2 receptors.2 The CRF1 receptor is abundantly found in the pituitary and is involved in the regulation of adrenocorticotropic hormone (ACTH), a key mediator of stress response.3 There is much evidence that CRF and CRF1 receptors are heavily involved in stress-related disorders such as depression and anxiety. In fact, it was shown that intracerebroventricular administration of CRF in rodents elicits behavioral and physiological effects identical to those caused by natural stressors.4 Furthermore, elevated CRF concentration in CSF has been observed in patients with depression5 and decreased expression of CRF receptor in the frontal cortex has been observed in suicide victims.6 Therefore, several pharmaceutical research groups have focused on the discovery of CRF1 receptor antagonists for the treatment of depression or other stress-related disorders. Meanwhile, the benefits of blocking the CRF2 receptor remain uncertain. To date, several CRF1 receptor antagonists have been reported and prototypical antagonists are illustrated in Figure 1. CRF1 receptor antagonists 1 (R121919),7 2 (CP-154526),8 3 (DMP696),9 4 (NBI-27914),10 and 5 (CP-316311)11 exhibited high in vitro affinity to the receptor and significant activity in animal models. However, clinical studies remain ambiguous. Antagonist 1 demonstrated efficacy in treating depressed patients in an open-label phase 2 clinical trial,12 but 5 was unsuccessful in a double-blind study for depression.13 From these results, it is apparent that the discovery of structurally diverse CRF1 receptor antagonists and the accumulation of clinical studies for clarifying the role of CRF in humans are essential.
Known CRF1 receptor antagonists have common structural features as illustrated in Figure 2. Each has a top region occupied by an alkyl chain, a central ring system occupied by a mono- or biheteroaromatic core, a small pocket occupied by a methyl group, and a bottom region occupied by a substituted phenyl or heteroaromatic moiety. Accordingly, we hypothesized that these four structural features were essential for CRF1 receptor antagonism. As a result of compound design based on this hypothesis, we previously reported compound 6 as a novel CRF1 receptor antagonist (Fig. 2).14 This compound exhibited potent in vitro activity and in vivo efficacy by oral administration. However, the unacceptable physicochemical profile (e.g., low aqueous solubility at pH 7.4) rendered this compound unsuitable for further development. Herein, we describe the results of our efforts to resolve this issue. Key sites in 6 were derivatized to generate a new series of compounds and the relationships between structure and solubility were examined. Studies of the structure–activity relationships, physicochemical properties, and electrostatic potentials of the derivatives are discussed. The biological activities of some of the new compounds were also examined, revealing a new analog with well-balanced solubility and in vitro efficacy.
Section snippets
Chemistry
Derivatives with a methyl substituent at the C8 position were synthesized as shown in Scheme 1. Nitration of commercially available compound 7 afforded 5-nitroquinoline 8. The position of the nitro group was determined by NMR analysis (Fig. 3). All of the proton and carbon signals of compound 8 were assigned by HMBC, COSY, and NOESY analysis. Next, the Suzuki–Miyaura cross-coupling reaction of 8 with [2,6-dimethoxy-4-(methoxymethyl)phenyl]boronic acid gave compound 9. Reduction of the nitro
Results and discussions
The compounds in this study were first screened for their ability to inhibit [125I] CRF binding to membranes of cells expressing the human CRF1 receptor. Compounds with high binding affinity were then subjected to an in vitro functional assay to evaluate their antagonistic functions in the inhibition of CRF-induced cAMP (cyclic adenosine monophosphate) production in human CRF1-receptor-expressed HEK293 cells.
The explorations initially performed were aimed at investigating the effects of
Conclusions
Through the preparation and evaluation of compounds derivatized at each site (R2, R3, R5, R5’, and R8), SAR and the relationships between structure and aqueous solubility were investigated. In the study of derivatization at the C8 position, it was revealed that introduction of a methoxy substituent overcame the issue of low aqueous solubility observed in previously reported compound 6, without loss of in vitro activity. In the 8-methoxyquinoline series, it was revealed that lowering
General methods
1H and 13C NMR spectra were recorded on a Bruker Avance spectrometer (operating at 600 MHz for 1H and 151 MHz for 13C). Chemical shifts were expressed in ppm (δ) from the residual CHCl3 signal at δH 7.26 ppm and δC 77.0 ppm in CDCl3 (s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, and b = broad). Coupling constants (J) are given in Hertz (Hz). IR spectra were obtained using the KBr method and the attenuated total reflectance (ATR) method with an FT/IR-620 spectrometer (JASCO). Only the
Acknowledgements
The authors would like to thank the colleagues who helped to generate all of the data reported in this manuscript. In particular, special thanks are owed to Eri Ena, Satoko Sasaki, Mami Gomibuchi, Nao Shibuguchi, and Yumi Yokoyama for NMR, HRMS, and IR analyses.
References and notes (18)
- et al.
Science
(1981) - et al.
Proc. Natl. Acad. Sci. U.S.A.
(1993)et al.Endocrinology
(1993)et al.Proc. Natl. Acad. Sci. U.S.A.
(1995)et al.Neuron
(1993) - et al.
Trends Pharmacol. Sci.
(1996)et al.Proc. Natl. Acad. Sci. U.S.A.
(1921)et al.Dev. Neurosci.
(1995) - et al.
Brain Res. Rev.
(1990) - et al.
Science
(1984) - et al.
Arch. Gen. Psychiatry
(1988) - et al.
J. Med. Chem.
(2004) - et al.
Proc. Natl. Acad. Sci. U.S.A.
(1996)et al.Eur. J. Pharmacol.
(1997) - et al.
J. Med. Chem.
(2000)
Cited by (6)
Dehydrogenative etherification homocoupling of heterocyclic N-oxides
2018, Tetrahedron LettersQuinoline N-Oxide: A Versatile Precursor in Organic Transformations
2022, ChemistrySelectRegioselective Chlorination of Quinoline N-Oxides and Isoquinoline N-Oxides Using PPh<inf>3</inf>/Cl<inf>3</inf>CCN
2016, European Journal of Organic ChemistryDevelopment of 8-benzyloxy-substituted quinoline ethers and evaluation of their antimicrobial activities
2015, Medicinal Chemistry ResearchCarbon trifluoromethylation reactions of hydrocarbon derivatives and heteroarenes
2015, Chemical Reviews