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Drug Discov Today. Author manuscript; available in PMC May 1, 2011.
Published in final edited form as:
PMCID: PMC2864802
NIHMSID: NIHMS184385
Progress in corticotropin-releasing factor-1 antagonist development
Eric P. Zorrilla and George F. Koob
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA
Corresponding author: Zorrilla, E.P. (ezorrilla/at/scripps.edu)
Corticotropin-releasing factor (CRF) receptor antagonists have been sought since the stress-secreted peptide was isolated in 1981. Although evidence suggests the limited efficacy of CRF1 antagonists as antidepressants, CRF1 antagonists might be novel pharmacotherapies for anxiety and addiction. Progress in understanding the two-domain model of ligand–receptor interactions for CRF family receptors might yield chemically novel CRF1 receptor antagonists, including peptide CRF1 antagonists, antagonists with signal transduction selectivity and nonpeptide CRF1 antagonists that act via the extracellular (rather than transmembrane) domains. Novel ligands that conform to prevalent pharmacophore and exhibit drug-like pharmacokinetic properties have been identified. The therapeutic utility of CRF1 antagonists should soon be clearer: several small molecules are currently in Phase II/III clinical trials for depression, anxiety and irritable bowel syndrome.
Corticotropin-releasing factor (CRF) receptor antagonists have been sought since Vale and colleagues isolated the stress-secreted, adrenocorticotropin-releasing hypothalamic peptide in 1981 [1]. The identification of CRF was followed by the discovery of genes encoding three paralogs of CRF (urocortins 1, 2 and 3; Ucn 1, Ucn 2 and Ucn 3) and two G-protein-coupled receptors (CRF1 and CRF2) that the CRF/Ucn[E1] peptides bind and activate with varying affinities [2,3]. Pharmacological and transgenic studies show that brain and pituitary CRF1 receptors mediate endocrine, behavioral and autonomic responses to stress [4]. Consequently, the pharmaceutical industry has sought to develop blood–brain-barrier-penetrating, selective CRF1 receptor antagonists [5]. Previous reviews by us and others have surveyed the biology of CRF systems [2]; the pharmacophore, physiochemical properties and pharmacokinetics of prototypical non-peptide CRF1 receptor antagonists [69]; and the therapeutic potential of CRF1 antagonists for stress-related indications [6,10,11], including major depression [12], anxiety disorders [13] and irritable bowel syndrome [14]. This article, after briefly overviewing the CRF/Ucn system and preclinical data supporting the therapeutic potential of CRF1 antagonists for anxiety, depression and addictive disorders, reviews advances in CRF1 antagonist development since 2005.
CRF-related peptides interact with two known mammalian CRF receptor subtypes, CRF1 and CRF2, which both belong to the class B1 (‘secretin-like’) subfamily of G-protein-coupled receptors. The CRF1 receptor exists in multiple isoforms (e.g. CRF1a–CRF1h), with the best known and functional isoform the CRF1(a) subtype. The CRF2 receptor has three known functional membrane-associated subtypes in humans – CRF2(a), CRF2(b) and CRF2(c) – and a ligand-sequestering, soluble CRF2(a) isoform discovered in mouse. CRF1 and CRF2 receptors have ~70% sequence identity. CRF has high, preferential affinity for CRF1 vs. CRF2 receptors. Ucn 1 is a high-affinity agonist at both receptors, and the type 2 urocortins (Ucn 2 and Ucn 3) are more selective for membrane CRF2 receptors. The biological actions of CRF, Ucn 1 and Ucn 2 in rodents are also modulated by a CRF-binding protein (CRF-BP), a 37-kDa secreted glycoprotein that binds and putatively immunosequesters CRF and Ucn 1 with equal or greater affinity than CRF receptors. Structural requirements for binding to CRF receptors and the CRF-BP differ. Many (if not most) CRF receptor antagonists do not bind the CRF-BP [3,6].
CRF1 receptors mediate not only the hypothalamic–pituitary–adrenal (HPA) axis neuroendocrine response to stress but also other aspects of stress responses in organisms. The distribution of CRF1 receptors in the brain is highly conserved in stress-responsive brain regions, including the neocortex, central extended amygdala, medial septum, hippocampus, hypothalamus, thalamus, cerebellum, and autonomic midbrain and hindbrain nuclei. This receptor distribution, concordant with that of its natural ligands CRF and Ucn 1, is consistent with the recognized role for extrahypothalamic CRF1 receptors in behavioral and autonomic stress responses.
Nonpeptide CRF1 antagonists consistently produce anxiolytic-like effects in animal models [6]. For example, in rodents, the compounds reduced conditioned fear [15,16], shock-induced freezing [17], anxiety-like responses to neonatal isolation [18,19] and defensive burying behavior [20,21]. CRF1 antagonists reduced acoustic startle responding [22,23] and showed efficacy in exploration-based models of anxiety, such as the open field, elevated plus maze, light–dark box and defensive withdrawal tests [18,2427], under stressed, but not non-stressed, testing conditions. CRF1 antagonists only exhibited weak activity in punished drinking and punished crossing conflict models (unlike γ-aminobutyric acid anxiolytics) [18,28] but effectively increased social interaction [28,29]. In rodents, little tolerance to the anxiolytic-like actions of CRF1 antagonists is observed with daily administration for up to 14 days [6]. CRF1 antagonists also blocked pain-related synaptic facilitation and anxiety-like behavior [30,31]. In addition, the compounds produced anxiolytic-like effects in intruder tests using non-human primate models [32,33].
Despite initial positive results, however, data with small-molecule CRF1 antagonists have not consistently shown efficacy in animal models that predict antidepressant activity [5]. Regarding positive findings, subchronic treatment with DMP696 and R121919 reduced forced swim immobility in mice [34], and chronic treatment with SSR125543 increased swimming in Flinder Sensitive Line rats, a putative genetic model of depression [35]. Acute antalarmin treatment similarly reduced forced swim immobility in CRF2-receptor-null mutant mice [36], and antalarmin, SSR125543A, LWH234 and CRA1000 acutely reduced immobility in some, but not all, studies of outbred rats [18,37,38]. R278995 reduced hyperemotionality of olfactory bulbectomized rats [39], a putative model of depression [40]. Chronic treatment with antalarmin or SSR125543A also improved coat appearance and reversed reductions in hippocampal neurogenesis in a mouse model of chronic mild stress [18,41,42].
Regarding negative findings, R121919, CP154,526 and R278995 failed to reduce forced swim immobility in rats [38,39], and antalarmin, CP-154,526, DMP904, R121919 and DMP696 failed to reduce forced swim immobility in mice after acute, subchronic or chronic (16 days) dosing [34,43,44]. Furthermore, antalarmin, CP-154526, DMP904, R121919, DMP696 and R278995 were all inactive in the tail suspension test with acute dosing [34,39,45]. Although acute treatment with CP-154526 was first reported to produce antidepressant-like effects in the learned helplessness paradigm [46], a subsequent study with CP-154526 failed to replicate this finding [47]. DMP904, DMP696 and CRA1000 were also inactive in this model after acute dosing [47,48]. Nonetheless, CP-154526, CRA1000 and R2789995 prevented the acquisition, but not the expression, of learned helplessness [39,47,49]. R278995 did not produce antidepressant-like effects in the rat differential-reinforcement-of-low-rate 72-s model [39]. A potential explanation for these mixed findings is that CRF1 antagonists might only exhibit antidepressant-like activity in ‘dysfunction’ models or models that exhibit a depressive-like endophenotype as a result of the animals’ genetic background or environmental manipulation (e.g. olfactory bulbectomy) and not in healthy, normal animals. Such an interpretation is consistent with findings showing that CRF1 antagonists differentially reduce anxiety-like behavior in models of high anxiety [6] and reduce drug or ethanol intake in models of dependence [5058], rather than in healthy, nondependent animals; however, this interpretation might be difficult to reconcile with the inability of CRF1 antagonists to reproducibly reverse learned helplessness behavior that results from repeated inescapable shock. A better understanding of the preclinical conditions under which CRF1 antagonists exert antidepressant-like effects might have translational implications for identifying patient subgroups or conditions under which CRF1 antagonists are more likely to be clinically useful for depression.
Another major action of CRF1 antagonists has been in the context of the activation of brain stress systems in addiction. As reviewed recently [59], both conceptual and neurobiological advances suggest that CRF1 systems contribute to the withdrawal–negative affect and preoccupation–anticipation (‘craving’) stages of the addiction cycle that fuel compulsive drug taking. Regarding the withdrawal–negative affect stage, dysphoria and increased anxiety are associated with both acute and protracted abstinence from most drugs of abuse. Such negative emotional symptoms, via negative reinforcement, drive high levels of drug taking to prevent or relieve the aversive withdrawal state, which is hypothesized to be mediated by CRF1 activation. Consistent with this hypothesis, both the HPA axis and extrahypothalamic CRF systems are activated during acute withdrawal from all major drugs of abuse in animal models [60], and central infusion of non-peptide CRF antagonists block the anxiogenic-like responses observed during acute withdrawal from drugs of abuse, including cocaine, alcohol, nicotine and cannabinoids [61]. Similarly, systemic administration of blood–brain-barrier-penetrating CRF1 antagonists reduced the anxiogenic-, aversive- and hypohedonic-like effects of withdrawal from opioids [6265], nicotine [56,66], benzodiazepines [63] and alcohol [29,54,55,67,68]. Supporting the motivational significance of withdrawal-associated CRF1 system activation for drug taking, administration of small-molecule CRF1 antagonists also reduced the excessive drug intake associated with dependence on alcohol [5055,69], nicotine [56], cocaine [57] and opioids [58]. Relatedly, CRF1 antagonists might also have therapeutic potential in individuals who self-medicate innate negative emotional states by taking excessive amounts of drugs or alcohol. This claim is supported by the anti-drinking efficacy of small-molecule CRF1 antagonists selectively in rats that show high innate anxiety, such as Marchigian alcohol-preferring rats [70] and isolation-reared Fawn-Hooded rats [71].
Stress is a major recognized precipitant of relapse, and CRF1 antagonists, therefore, are also hypothesized to have therapeutic potential in the ‘craving’ stage of the addiction cycle by preventing stress-induced relapse. Accordingly, non-peptide CRF antagonists centrally block stress-induced reinstatement of drug-seeking behavior in animal models [72]. Similarly, systemic administration of small-molecule CRF1 antagonists reduced footshock stress-induced reinstatement of heroin-, cocaine-, nicotine-or alcohol-seeking behavior in rats [55,66,7375] and footshock stress-induced reactivation of conditioned place preference for opioids and cocaine [76,77]. Thus, models of drug withdrawal, excessive drug taking, innate anxiety with comorbid ethanol intake and stress-induced relapse behavior all support the therapeutic potential of CRF1 antagonists for drug dependence.
Several N-terminally truncated and substituted analogs of CRF act as subtype nonselective competitive partial agonists or full antagonists at CRF receptors. Examples of these, in chronological order of discovery, include the partial agonist [Met18, Lys23, Glu27,29,40, Ala32,41, Leu33,36,38] r/hCRF9-41 (α-helical CRF9-41) and the full receptor antagonists [D-Phe12, Nle21,38 CaMeLeu37] r/hCRF12-41 (D-Phe CRF12-41), cyclo(30-33)[D-Phe12, Nle21,38, Glu30, Lys33] r/hCRF12-41 (astressin) and cyclo(30-33)[D-Phe12, Nle21, CaMeLeu27, Glu30, Lys33, Nle38, CaMeLeu40]Ac-r/hCRF9-41 (astressin-B). These peptide ligands have approximately the same order of binding and antagonist potency at CRF1 vs. CRF2 receptors and do not cross the blood–brain barrier. Thus, they are subtype nonselective, peripherally acting CRF receptor antagonists.
An emerging development within the last five years is that in the course of seeking minimal fragments of CRF that retain antagonist activity, CRF1-preferring peptide antagonists might have been identified. Yamada and colleagues [78] followed up a Solvay patent application [79] that described a peptide comprising the 12 C-terminal residues of astressin as a potent antagonist of CRF receptors. Through amino acid substitution of Nle38 with a lipophilic cyclohexylalanine residue and Ala31 with an unnatural residue (D-Ala), they identified a metabolically stable, high-affinity (Ki ~3 nM) CRF1 antagonist that potently (0.1 mg/kg, i.v.) reduced adrenocorticotropic hormone secretion in a rat sepsis model. This peptide might be a CRF1-preferring antagonist; the Solvay group concurrently reported that the 12-residue N-terminal truncated astressin derivative from which Yamada and colleagues began their studies retains CRF1 affinity but is inactive at the CRF2(a) receptor.[E2] Thus, lactam-bridge-constrained N-terminally truncated astressin derivatives of 12–15 residue length might be preferential CRF1 receptor peptide antagonists. Such compounds could be useful for the treatment of pathologies associated with peripheral CRF1 hyperactivation [80], perhaps including irritable bowel syndrome, premature labor, postoperative gastric ileus, and Cushingoid aspects of severe alcohol dependence, visceral obesity, melancholic major depression and anorexia nervosa [5].
Progress has also been made in understanding the mode of ligand–CRF1 receptor interaction. Natural peptide agonists of CRF receptors are thought to bind and activate the receptor via a two-site mechanism. The carboxyl end of the agonist first binds the N-terminal first extracellular domain (ECD1) (‘N-domain’), and the amino portion of the ligand successively binds the extracellular face of the seven juxtamembrane regions (‘J-domain’), stabilizing an agonist-bound, ‘active’ receptor state that yields signal transduction [81,82]. Interaction with the J-domain might also be important for receptor internalization because short (e.g. 12-residue) C-terminal peptide antagonists that only bind the N-domain do not trigger endocytosis, unlike longer antagonists that also interact with the J-domain (e.g. astressin) [83].
Recently, a minimal cyclic peptide fragment homologous to the 12 C-terminal residues of astressin was used to understand determinants of ligand binding to the N-domain of the CRF1 receptor recombinantly isolated from the J-domain [84]. NMR spectroscopy showed that two hydrophobic residues (Met38 and Ile41 of CRF sequence) and two amide groups (Asn34 and the C-terminal amide) on one face of the bound peptide’s α helix defined the antagonist’s binding epitope. This epitope could potentially be used as a template to develop novel non-peptide competitive antagonists that target the agonist-binding N-domain of the CRF1 receptor, in contrast to existing small-molecule antagonists that allosterically target the J-domain [82].
Recently, different ligands have been shown to address the J-domain of the receptor differently, conferring not only receptor subtype selectivity but also signal transduction pathway selectivity within a given receptor subtype. For example, the NMR solution structures of astressin B, astressin2-B and Ucn 2 exhibit a large (90°) kink that, after binding to the N-domain, orients the ECD1 with its positively charged face toward the negatively charged extracellular loops 2, 3 and 4 of the receptor. By contrast, astressin, stressin1, hUcn1 and hUcn3 have no or much smaller kinks, such that the ECD1 of the receptor would have to orient at a different angle to enable ligand interaction with the J-domain. Grace and colleagues hypothesized that the different ligand–receptor complex confirmations could lead to engagement of different signal transduction pathways [85]. Supporting this hypothesis, single substitutions of Ucn 1 with bulky amino acids (e.g. benzoyl-phenylalanine or naphthylalanine) in residues 6–15, but not at other positions, eliminated the peptide’s ability to stimulate Gi–protein activation while not altering its activation of Gs–protein pathways. The resulting analogs were competitive receptor antagonists for the Gi–protein pathway and agonists for the Gs pathway [86]. Similarly, the nonpeptide antagonist antalarmin, which binds the J-domain of the receptor, had different antagonist potency against urocortin- vs. sauvagine-induced G-protein activation and also exhibited different modes of antagonist action: competitive for receptor coupling to Gs but noncompetitive for Gi activation. By contrast, the peptide antagonist α-helical CRF9-41, which binds the peptide agonist-binding N-domain, uniformly and competitively antagonized urocortin- or sauvagine-induced activation of both Gi and Gs signaling pathways [87]. These results suggest that antagonism of specific CRF1 signal transduction pathways might be possible via ligands that stabilize or destabilize particular ligand–receptor complex confirmations[E3].
A final recent finding regarding the mode of CRF antagonist action was that nonpeptide ligands can allosterically facilitate or inhibit binding of CRF to G-protein-uncoupled CRF1 receptors while uniformly inhibiting signaling efficacy in the CRF-bound, active, G-protein-coupled state. Positive and negative allosteric modulators of CRF affinity for the uncoupled receptor functioned as intrinsic weak agonists or inverse agonists at uncoupled receptors, respectively. Thus, different conformational states can lead to inhibition of CRF signaling. Nonpeptide ligands can act as functional antagonists by stabilizing an inactive (allosteric inverse agonist) or weakly active (allosteric agonist) receptor state, either of which can shift receptor equilibrium away from the CRF-bound, fully active signaling state [88].
Pharmacophore and selectivity
Since 2005, many small molecules with high and selective CRF1 (vs. CRF2) affinity have been identified (Table 1). Each series follows the previously reviewed general pharmacophore common to most nonpeptide CRF1 antagonists. Prototypical compounds (Figure 1) share one or two aliphatic top units that occupy a hydrophobic pocket of the receptor, a central mono-, bi- or tricyclic ring core and an orthogonal, conformation-stabilizing 2,4-di- or 2,4,6-tri-substituted aromatic bottom group. Each ring core contains a putative proton-accepting ring nitrogen separated from the pendant aromatic by a one- or, more commonly, two-atom spacer. The core ring is typically methylated on the opposite position adjacent to the bonding nitrogen. The hydrogen bond accepting core nitrogen is hypothesized to interact with the imidazole side chain of histidine-199, a polar amino acid in the third transmembrane domain of the CRF1 receptor that is not shared in the CRF2 receptor or CRF-BP sequences. Nonpeptide antagonists of this pharmacophore also require the rotational flexibility present in methionine residue 276 of the CRF1 (and not CRF2) receptor sequence [89], putatively to permit a hydrophobic interaction of the ring core with the fifth transmembrane domain. Accordingly, mutation of the 199 or 276 CRF1 residues (His-199, Met-276) to their corresponding CRF2 amino acids (Val-199, Ile-276) reduced the binding affinity of the selective CRF1 antagonist NBI 27914 by 40- and 200-fold, respectively [90]. A computational model incorporating both structural interaction features recently yielded good affinity predictions for a series of dihydropyridopyrazinone and dihydropteridinone CRF1 antagonists (r2 = 0.71) [91]. An independent in silico receptor docking model reached a similar conclusion regarding the structural mode of antagonist action for diydropyrrolo[2,3-d]pyrimidines [92]. Thus, nonpeptide antagonists of the prevalent pharmacophore seem to be potent and selective CRF1 antagonists in relation to their interactions with features in the third (His-199) and fifth (Met-276) transmembrane receptor domains.
Table 1
Table 1
Selected novel nonpeptide CRF1 antagonists in recent peer-reviewed literature (2005–2009)a
Figure 1
Figure 1
Prototypical CRF1 antagonists.
Previously reviewed compounds that depart significantly[E4] from the pharmacophore include oxo-7H-benzo[e]pyrimidine-4-carboxylic acid derivatives (subtype nonselective CRF receptor antagonists discovered by Alanex), CC 2064460 (a moderately potent arylamidrazone CRF1 antagonist that lacks a central ring core with the customary hydrogen-bond-accepting nitrogen[E5]) and stereospecific N-phenylphenylglycines (which also lack a ring core but were identified through computational screening based on a classic pharmacophore training set [6]).
Lipophilicity and pharmacokinetic properties
As we and others have reviewed previously, clinical development of nonpeptide CRF1 antagonists has been hampered because most leads were undesirably lipophilic, with poor water solubility and pharmacokinetic properties [6,9]. Most early CRF1 antagonists failed Lipinski’s ‘rule of five’ criteria for drug candidates because of excessive lipophilicity (cLogP > 5). This benchmark is relevant because of more than 100 drugs marketed as of 1992 for CNS indications, not one had a logD > 4, which can yield poor physiochemical and pharmacokinetic properties. Rather, most (~85%) had a logD of 0–3. Preclinical studies since 2005, therefore, have sought to identify less hydrophobic, more drug-like CRF1 antagonists with favorable pharmacokinetic properties and fewer anticipated toxicities.
Table 1 shows pharmacological, physiochemical and pharmacokinetic properties of several nonpeptide CRF1 receptor antagonists from recent peer-reviewed literature (2005–2008). Many exemplar antagonists continue to exhibit low blood–brain barrier penetration (e.g. brain/plasma [B/P] ratios < 1), poor oral bioavailability (F% < 20%), high volumes of distribution at steady state (VD > 10 L/kg) and high plasma clearance (Clplasma > 45 ml/min/kg) [93]. However, several compounds exhibited more favorable overall pharmacokinetics. One compound from Neurocrine Biosciences was a potent (Ki = 2 nM), albeit rapidly cleared, imidazo[4,5-b]pyridin-2-one with good blood–brain barrier penetration (B/P = 2.8; compound 16g in Ref. [94]). Several from GlaxoSmithKline were less potent (IC50 = 32–100 nM) substituted tetrahydrotetraazaacenaphthylenes and diydropyrrolo[2,3-d]pyrimidines with excellent oral bioavailability (52%–86%), distribution/clearance balance[E6] and central accumulation (B/P = 2.3–3.7), including the clinical candidate GW876008 (see below) [95]. Two from Pfizer were potent (Ki = 5–7 nM) 2-aryloxy-4-alkylaminopyridines, including the clinical candidate CP-316311 (see below) [96] and a successor with better solubility at stomach pH and food-independent oral bioavailability (compound 3a in Ref. [97]). An Eli Lilly and NIAAA collaboration yielded a highly potent (Ki = 0.22 nM) imidazo[1,2-b]pyradizine, with outstanding oral bioavailability (91%; MTIP[E7]) [55]. Finally, Bristol Myers Squibb advanced two promising substituted pyrazolo[1,5-a]-1,3,5-triazines to clinical trials (BMS-561388 and their current lead candidate BMS-562086 [Pexacerfont], IC50 = 6.1 nM), which showed good pharmacokinetics in rat, dog and non-human primate models, no evidence of gastrointestinal or respiratory toxicity, and mild renal effects at doses approximately one order greater than those needed to substantially occupy brain CRF receptors [98]. Each of these compounds was active in vivo at minimum effective oral doses of 2–10 mg/kg in preclinical behavioral or endocrine animal models that are sensitive to CRF1 signaling (Table 1).
Patent literature
As shown in Table 2, small-molecule CRF1 antagonists disclosed recently in the patent literature (2006–2008) are also variations on the prevalent pharmacophore. Newer compounds have involved different cores, including heterocyclic pyrrolotriazinones (e.g. WO 2008136377), benzimadole derivatives (e.g. WO 2008082003, WO 2008051533 and WO 2006116412) and pyrazolo[4,3-d]pyrimidines (e.g. WO 2006126718), as well as monocyclic indanylaminopyrazinypyridines (e.g. US 2006211710). In each of these variants, the proton-accepting nitrogen is present in the cycle adjacent to, rather than distal from, the ‘down’ aromatic (Table 2), which might allow for new substitution chemistries. Another development has been clear confirmation that the ‘top’ unit does not need to be branched alkyl chains (a feature that contributed to the undesirably high lipophilicity of the pharmacophore) but rather can tolerate polar, cyclic amines and related structures (e.g. WO2007039264, WO2006001501, WO2006001511, WO2006126718 and US2006211710). ‘Down’ units that are less lipophilic than the prototypical di- and tri-substituted phenyl aromatic are also now common antagonist features, including sulfur- and nitrogen-containing substituted rings (e.g. WO2008036579, WO2008036541, WO2006102194 and US2006211710).
Table 2
Table 2
Recent clinical trials for CRF1 antagonists
Clinical development
Several CRF1 antagonists from different pharmaceuticals have entered clinical trials since December 2004. Because an open-label Phase IIa trial showed that escalating doses of R121919 exhibited a good overall safety profile, normalized sleep EEG[E8] and reduced depressive and anxious symptoms in depressed patients [6], clinical anticipation of CRF1 antagonists has been high. However, R121919 development was discontinued because of isolated instances of elevated liver enzymes in a parallel trial. Despite major efforts (Table 3), no subsequent CRF1 antagonist has successfully completed a definitive Phase III trial. By contrast, development of ONO-2333Ms and CP-316311 were discontinued because of negative efficacy results in double-blind, placebo-controlled trials for major depression [99]. Currently, the number of additional CRF1 antagonists that are undergoing or have completed undisclosed efficacy trials (Phase II/III) is at least three for major depression (GSK561679, GW876008 and Pexacerfont) and two for irritable bowel syndrome and social anxiety disorder (GSK561679 and GW876008).[E9] Several other candidates are earlier in the pipeline or their status has not been publicly updated by the pharmaceutical industry (e.g. GSK586529, TAI-041/JNJ19567470, SSR125543, NBI-34101 and antalarmin). Results from these trials should provide definitive conclusions regarding the therapeutic potential of CRF1 antagonists for anxiety, depression and irritable bowel disorder and might pave the way for clinical evaluation in addictive disorders.
Table 3
Table 3
Selected recent patents for CRF1 antagonists (2006–2008)
Acknowledgments
This is publication number 21067 from The Scripps Research Institute. Research was supported by National Institutes of Health grants DK26741 and DK070118 from the National Institute of Diabetes and Digestive and Kidney Diseases. The authors thank Michael Arends and Mellany Santos for their help with manuscript preparation.
Footnotes
Disclosure statement
E.P.Z. and G.F.K. are inventors on a provisional patent filed for CRF1 antagonists (application serial #9709/102,422). G.F.K. currently provides consulting services to Alkermes, Boehringer-Ingelheim, Embera Pharmaceuticals, GlaxoSmithKline and Eli Lilly.
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