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`ELSEVIER
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`Progress in corticotropin-releasing
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`factor-1 antagonist development
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`Eric P. Zorrilla and George F. Koob
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`Corticotropin releasing factor (CRF) receptor antagonists have been sought since the stress-secreted
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`as peptide was isolated in 1981. Although evidence is mixed concerning the efficacy of CRF1 antagonists
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`for anxiety and addiction. antidepressants, might be novel pharmacotherapies CRF1 antagonists
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`Progress in understanding the two-domain model of ligand-receptor interactions for CRF family
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`including peptide antagonists, receptors might yield chemically novel CRF1 receptor CRF1 antagonists,
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`that act via the antagonists with signal transduction selectivity and nonpeptide CRF1 antagonists
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`extracellular (rather than transmembrane) domains. Novel ligands that conform to the prevalent
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`pharmacophore and exhibit drug-like pharmacokinetic properties have been identified. The therapeutic
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`in Phase 11/111 are currently several small molecules should soon be clearer: utility of CRF1 antagonists
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`clinical trials for depression, anxiety and irritable bowel syndrome.
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`Biology of CRF/Ucn receptor systems
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`Corticotropin releasing factor (CRF) receptor antagonists have been
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`sought since Vale et al. isolated the stress-secreted, adrenocortico­CRF-related peptides interact with two known mammalian CRF
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`tropin-releasing hypothalamic peptide in 1981 [l]. The identifica­receptor subtypes, CRF1 and CRF2, which both belong to the class
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`tion of CRF was followed by the discovery of genes encoding three Bl (secretin-like) subfamily of G-protein-coupled receptors. The
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`isoforms (e.g. exists in multiple paralogs of CRF (urocortins 1, 2 and 3; Ucn 1, Ucn 2 and Ucn 3) and CRF1 receptor CRF13-CRF1h), with
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`(CRF1 and CRF2) that the CRF/Ucn
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`the best known and functional isoform the CRFi(a) subtype. The
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`two G-protein-coupled receptors
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`membrane-associated has three known functional peptides bind and activate with varying affinities [2,3]. Pharmaco­CRF2 receptor
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`logical and transgenic studies show that brain and pituitary subtypes CRF1
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`in humans -CRFz(a), CRFz(b) and CRFz(c) -and a ligand­
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`discovered receptors mediate endocrine, behavioral and autonomic responses sequestering, soluble CRF2(a) isoform in mouse. CRF1
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`identity. CRF has high, have ~70% sequence to stress [4]. Consequently, the pharmaceutical industry has sought and CRF2 receptors
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`Ucn 1 is a high­to develop blood-brain-barrier-penetrating, selective preferential CRF1 receptor affinity for CRF1 versus CRF2 receptors.
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`antagonists [ 5]. Previous reviews by us and others have surveyed the affinity agonist at both receptors, and the type 2 urocortins (Ucn 2
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`biology of CRF systems [2]; the pharmacophore, physiochemical and Ucn 3) are more selective for membrane do CRF2 receptors.
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` The biological properties and pharmacokinetics of prototypical nonpeptide CRF1
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`actions of CRF, Ucn 1 and Ucn 2 in rodents are also
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`receptor antagonists [6-9]; and the therapeutic potential of CRF1
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`modulated by a CRF-binding protein (CRF-BP), a 37-kDa secreted
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`antagonists for stress-related indications [ 6, 10, 11 ], including major glycoprotein that binds and putatively immunosequesters CRF
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`depression [12], anxiety disorders [13] and irritable bowel syndrome and Ucn 1 with equal or greater affinity than CRF receptors.
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`[14]. This article, after briefly overviewing the CRF/Ucn system and
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`Structural requirements for binding to CRF receptors and the
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` CRF-BP differ. preclinical data supporting the therapeutic potential of CRF1
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`Many (if not most) CRF receptor antagonists do
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`antagonists for anxiety, depression and addictive disorders, reviews
`not bind the CRF-BP [3,6].
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`development since 2005. advances in CRF1 antagonist
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`CRF1 receptors mediate not only the hypothalamic-pituitary­
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`adrenal (HPA) axis neuroendocrine response to stress but also
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`other aspects of stress responses in organisms. The distribution of
`Corresponding author: The Scripps Research Institute, 1 OSSO North Torrey Pines Road, SP30-
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`in stress-responsive conserved CRF1 receptors in the brain is highly
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`2400, La Jolla, CA 92037, USA. Zorrilla, E.P. {ezorrilla@scripps.edu)
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`1359-6446/06/$ -see front matter� 2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.drudis.2010.02.011
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`Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA
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`REVIEWS
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`www.drugdiscoverytoda
`y.com 371
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`1
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`NEUROCRINE-1030
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`r4 REVIEWS
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`oy.)
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`Drug Discovery Todays Volume 15, Numbers 9/10* May 2010
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`brain regions, including the neocortex, central extended amygdala,
`medial septum, hippocampus, hypothalamus, thalamus, cerebel-
`lum, 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 extra-
`hypothalamic CRF,
`receptors in behavioral and autonomic
`stress responses.
`
`CRF, antagonists in animal models of anxiety,
`depression and addictive disorders
`Nonpeptide CRF, antagonists consistently produce anxiolytic-like
`effects in animal models [6]. For example, in rodents, the com-
`poundsreduced conditioned fear [15,16], shock-induced freezing
`[17], anxiety-like responses to neonatal isolation [18,19] and
`defensive burying behavior [20,21]. CRF, antagonists reduced
`acoustic startle responding [22,23] and showedefficacy in explora-
`tion-based models of anxiety, such as the openfield, elevated plus
`maze, light-dark box and defensive withdrawal tests [18,24-27],
`under stressed, but not nonstressed,
`testing conditions. CRF,
`antagonists only exhibited weak activity in punished drinking
`and punished crossing conflict models (unlike y-aminobutyric
`acid anxiolytics) [18,28] but effectively increased social interaction
`[28,29]. In rodents,little tolerance to the anxiolytic-like actions of
`CRF,antagonists is observed with daily administration for up to 14
`days [6]. CRF, antagonists also blocked pain-related synaptic
`facilitation and anxiety-like behavior [30,31]. In addition, the
`compounds produced anxiolytic-like effects in intrudertests using
`nonhumanprimate models [32,33].
`Despite initial positive results, however, data with small-mole-
`cule CRF, 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 $SR125543 increased swimming in Flinder
`Sensitive Line rats, a putative genetic model of depression [35].
`Acute antalarmin treatmentsimilarly reduced forced swim immo-
`bility in CRF,-receptor-null mutant mice [36], and antalarmin,
`$SR125543A, LWH234 and CRA1000acutely reduced immobility
`in some, but notall, studies of outbred rats [18,37,38]. R278995
`reduced hyperemotionality of olfactory bulbectomizedrats [39], a
`putative model of depression [40]. Chronic treatment with anta-
`larmin 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, CP-154526 and R278995
`failed to reduce forced swim immobility in rats [38,39], and
`antalarmin, CP-154526, DMP904, R121919 and DMP696failed
`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 wasfirst reported to
`produce antidepressant-like effects in the learned helplessness
`paradigm [46], a subsequent study with CP-154526failed to repli-
`cate 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
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`372 www.drugdiscoverytoday.com
`
`did not produce antidepressant-like effects in the rat differential-
`teinforcement-of-low-rate 72-s model [39]. A potential explana-
`tion for these mixed findings is that CRF, 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 manipula-
`tion (e.g. olfactory bulbectomy) and not in healthy, normal ani-
`mals. Such an interpretation is consistent with findings showing
`that CRF, antagonists differentially reduce anxiety-like behavior
`in models of high anxiety [6] and reduce drugor ethanolintake in
`models of dependence [50-58], rather than in healthy, nondepen-
`dent animals; however, this interpretation might be difficult to
`reconcile with the inability of CRF, antagonists to reproducibly
`teverse learned helplessness behavior that results from repeated
`inescapable shock. A better understanding of the preclinical con-
`ditions under which CRF, antagonists exert antidepressant-like
`effects might have translational
`implications for identifying
`patient subgroups or conditions under which CRF, antagonists
`are more likely to be clinically useful for depression.
`Another major action of CRF, antagonists has been in the
`context of the activation of brain stress systems in addiction. As
`teviewed recently [59], both conceptual and neurobiological
`advances suggest that CRF, systems contribute to the withdra-
`wal-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 preventor relieve the aversive withdrawal state, which is
`hypothesized to be mediated by CRF, activation. Consistent with
`this hypothesis, both the HPA axis and extrahypothalamic CRF
`systemsare activated during acute withdrawalfrom all major drugs
`of abuse in animal models [60], and central infusion of nonpeptide
`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 CRF, antago-
`nists reduced the anxiogenic-, aversive- and hypohedonic-like
`effects of withdrawal from opioids [62-65], nicotine [56,66], ben-
`zodiazepines [63] and alcohol [29,54,55,67,68]. Supporting the
`motivational significance of withdrawal-associated CRF, system
`activation for drug taking, administration of small-molecule CRF;
`antagonists also reduced the excessive drug intake associated with
`dependence onalcohol[S0-55,69], nicotine [56], cocaine [57] and
`opioids [58]. Relatedly, CRF, antagonists might also have thera-
`peutic potential in individuals whoself-medicate innate negative
`emotionalstates by taking excessive amounts of drugs or alcohol.
`This claim is supported by the anti-drinking efficacy of small-
`molecule CRF, antagonists selectively in rats that show high
`innate anxiety, such as Marchigian alcohol-preferring rats [70]
`and isolation-reared Fawn-Hoodedrats [71].
`Stress is a major recognized precipitant of relapse, and CRF,
`antagonists, therefore, are also hypothesized to have therapeutic
`potential in the ‘craving’ stage of the addiction cycle by preventing
`stress-induced relapse. Accordingly, nonpeptide CRF antagonists
`centrally block stress-induced reinstatement of drug-seeking beha-
`vior in animal models [72]. Similarly, systemic administration of
`
`2
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`acc
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`Drug Discovery Today* Volume 15, Numbers 9/10* May 2010
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`REVIEWS
`
`reduced footshock stress-
`small-molecule CRF, antagonists
`induced reinstatement of heroin-, cocaine-, nicotine- or alco-
`hol-seeking behavior in rats [55,66,73-75] and footshock stress-
`inducedreactivation 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 behaviorall support the therapeutic poten-
`tial of CRF, antagonists for drug dependence.
`
`Peptide CRF,-selective receptor antagonists
`Several N-terminally truncated and substituted analogs of CRF act
`as subtype nonselective competitive partial agonistsor full antago-
`nists at CRF receptors. Examples of these, in chronological orderof
`discovery, include the partial agonist [Met’®, Lys™*, Glu?”?9*0,
`Ala?241, Lew353638] r/hCRFo.4, (a-helical CRFs_4,) and the full
`receptor antagonists [p-Phe!?, Nle?*38 CaMeLeu?’] t/hCRFy241
`(p-Phe CRF12_41), cyclo(30-33) [p-Phe!”, Nle2138, Gtu3°, Lys?4] r/
`hCRF;24;
`(astressin) and cyclo(30-33)
`[p-Phe’”, Nle?’, CaMe-
`Leu?’, Glu®°, Lys33, Nle®®, CaMeLeu*®]Ac-r/hCRFo_41 (astressin-
`B). These peptide ligands have approximately the same order of
`binding and antagonist potency at CRF, versus 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 past five years is that in
`the course of seeking minimal fragments of CRF that retain
`antagonist activity, CRF,-preferring peptide antagonists might
`have been identified. Yamada ef al.
`[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 lipo-
`philic cyclohexylalanine residue and Ala31 with an unnatural
`residue (p-Ala), they identified a metabolically stable, high-affinity
`(K; ~3 nm) CRF, antagonist that potently (0.1 mg/kg,i.v.) reduced
`adrenocorticotropic hormonesecretion in a rat sepsis model. This
`peptide might be a CRF,-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 CRF, affinity but is inactive at the CRF2,)
`receptor. Thus, lactam-bridge-constrained N-terminally truncated
`astressin derivatives of 12-15 residue length might be preferential
`CRF, receptor peptide antagonists. Such compounds could be
`useful for the treatment of pathologies associated with peripheral
`CRF, 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 in the two-domain model of ligand-CRF,
`receptor interaction
`Progress has also been made in understanding the modeof ligand—
`CRF,receptor interaction. Natural peptide agonists of CRF recep-
`tors are thought to bind andactivate 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 juxtamembraneregions(J-domain), stabilizing an
`agonist-bound,‘active’ receptor state that yields signal transduc-
`tion [81,82]. Interaction with the /-domain might also be impor-
`
`tant 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 minimalcyclic peptide fragment homologousto the
`12 C-terminal residues of astressin was used to understand deter-
`
`minants of ligand binding to the N-domain of the CRF; 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 a helix defined the
`antagonist’s binding epitope. This epitope could potentially be
`used as a template to develop novel nonpeptide competitive
`antagonists that target the agonist-binding N-domain of the
`CRF, 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
`subtypeselectivity but also signal transduction pathwayselectivity
`within a given receptor subtype. For example, the NMRsolution
`structuresof astressin-B, astressin2-B and Ucn 2 exhibit a large (90°)
`kinkthat, after binding to the N-domain,orients the ECD1 withits
`positively charged face toward the negatively charged extracellular
`loops 2-4 of the receptor. By contrast, astressin, stressin,, 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 et al. hypothesized
`that the different ligand-receptor complex conformations could
`lead to the engagementof different signal transduction pathways
`[85]. Supporting this hypothesis, single substitutions of Ucn 1 with
`bulky amino acids (e.g. benzoyl-phenylalanine or naphthylala-
`nine) in residues 6-15, but not at other positions, eliminated the
`peptide’s ability to stimulate G;-protein activation while notalter-
`ing its activation of G,-protein pathways. The resulting analogs
`were competitive receptor antagonists for the G,-protein pathway
`and agonists for the G, pathway [86]. Similarly, the nonpeptide
`antagonist antalarmin, which binds the J-domainof the receptor,
`had different antagonist potency against urocortin- versus sauva-
`gine-induced G-protein activation and also exhibited different
`modes of antagonist action: competitive for receptor coupling
`to G, but noncompetitive for G, activation. By contrast, the pep-
`tide antagonist o-helical CRFy_41, which binds the peptide agonist-
`binding N-domain, uniformly and competitively antagonized
`urocortin- or sauvagine-induced activation of both G; and G,
`signaling pathways [87]. These results suggest that antagonism
`of specific CRF, signal transduction pathways might be possible
`via ligands that stabilize or destabilize particular ligand-receptor
`complex conformations.
`A final recent finding regarding the mode of CRF antagonist
`action was that nonpeptide ligandscan allosterically facilitate or
`inhibit binding of CRF to G-protein-uncoupled CRF, 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 and inverse agonists at uncoupled
`receptors, respectively. Thus, different conformational states can
`lead to the inhibition of CRF signaling. Nonpeptide ligands can act
`as functional antagonists by stabilizing an inactive (allosteric
`
`www.drugdiscoverytoday.com 373
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`3
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`Drug Discovery Today* Volume 15, Numbers 9/10* May 2010
`
`inverse agonist) or weakly active (allosteric agonist) receptorstate,
`either of which can shift receptor equilibrium away from the CRF-
`bound,fully active signaling state [88].
`
`Novel, nonpeptide CRF,-selective receptor antagonists
`Pharmacophoreandselectivity
`Since 2005, many small molecules with high and selective CRF,
`(versus CRF.) affinity have been identified (Table 1). Each series
`follows the previously reviewed general pharmacophore common
`to most nonpeptide CRF, 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 corering is typically methylated on the opposite
`position adjacent to the bonding nitrogen. The hydrogen-bond-
`accepting core nitrogen is hypothesized to interact with the imi-
`dazole side chain of histidine-199, a polar amino acid in the third
`
`transmembrane domain of the CRF, receptor that is not shared in
`the CRF, receptor or CRF-BP sequences. Nonpeptide antagonists of
`this pharmacophore also require the rotational flexibility present
`in methionine residue 276 of the CRF, (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 CRF, residues (His-199, Met-276) to
`their corresponding CRF, aminoacids (Val-199, Ile-276) reduced
`the bindingaffinity of the selective CRF, antagonist NBI 27914 by
`40- and 200-fold, respectively [90]. A computational model incor-
`porating both structural interaction features recently yielded good
`affinity predictions for a series of dihydropyridopyrazinone and
`dihydropteridinone CRF, antagonists (r” = 0.71) [91]. An indepen-
`dentin silico receptor docking model reached a similar conclusion
`regarding the structural mode of antagonist action for dihydro-
`pyrrolo[2,3-d]pyrimidines [92]. Thus, nonpeptide antagonists of
`the prevalent pharmacophore seem to be potent and selective
`CRF, antagonists partly in relation to their interactions with
`features in the third (His-199) and fifth (Met-276) transmembrane
`receptor domains.
`
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`NBI-30545
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`OncHs
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`2 REVIEWS
`Drug Discovery Today
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`MNDa
`
`NBI-27914
`
`HCNya~CHs oygCNN~~THs
`
`AX
`
`coe
`
`CP-154526
`
`Antalamin
`
`PD-171729
`
`HC.
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`HaC.
`
`;NH
`
`a nN.
`|
`S—CHs
`
`H3C Sy
`
`DMP-904
`
`Oo,
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`
`DMP-696
`
`FIGURE 1
`
`Prototypical CRF, antagonists.
`
`374 www.drugdiscoverytoday.com
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`4
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`

`
`
`TABLE1
`
`
`Selected novel nonpeptide CRF, antagonists in recent peer-reviewed literature (2005-2009)"
`
`
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`Company Vy—tyz (h) NotesCore Best CAS CRF, pK, clogP clog Dp7 clog Dgy-2 MW PSA Oral Cplasma Refs
`cycles exemplars
`_registry
`affinity
`(A)
`bioavailability (ml/min kg) (L/kg)
`(nm)
`(F%)
`
`
`1-Aryl-4-aminoalkylisoquinolines
`Neurogen
`Bi
`26k
`1012325-20-0 Ky=8
`584
`7.54
`752
`507
`4485 254 48
`145
`13
`54
`-
`[100]
`
`2-Arylpyrimidines
`Neurogen
`Mono 12b
`1067229-15-5 Ky=9
`-
`500
`-
`-
`380.9 -
`6
`13.6
`14
`8
`-
`[101]
`1-Methyl3-dialkylamino-5-
`Neurocrine Mono 7r
`848648-99-7
` Ky=7
`465
`7.17
`7A7
`485
`445.0 43.2 84
`277
`78
`33
`B/P = 0.20
`[102]
`
`aryltriazoles
`
`Pyrrolo[2,3-b]pyridine-based tricyclics Neurocrine—Tri 19g 374798-46-6 Ki=3.5 9.34 837 625 587 396.0 21.1 24 70 38 63 B/P = 0.27; [103]
`
`
`
`
`
`
`
`
`
`
`
`reduced restraint-induced
`
`ACTH (10 mg/kg)
`
`Pyrazolo[3,4-b]pyridine-based tricyclics Neurocrine—Tri 22a 877672-44-1 Ky=2.9 1341 5.43 3.43 243 4194 312 7 43 44 12 B/P = 0.53; [103]
`
`
`
`
`
`
`
`
`
`
`reduced restraint-induced
`
`ACTH (10 mg/kg)
`
`
`Imidazo/[4,5-6]pyridin-2-ones Neurocrine=Tri 16g 268539-94-2 Ky=2 10.78 2.45 -0.03 0.05 394.5 48.9 30 53 72 16 B/P = 2.8; reducediv, [94]
`
`
`
`
`
`
`
`
`
`
`CRF-induced ACTH
`
` (10 mg/kg)
`
`
`Tetrahydrotetraazaacenaphthylenes Neurocrine=Tri 12a 603151-83-3 Ky=3 791 514 419 2.64 401.3 29.0 34 17 178 «12 B/P = 1.25; reduced [104]
`
`
`
`
`
`
`
`
`
`
`
`(NBI35965)
`(free base)
`restraint oriv. CRF-induced
`ACTH (10-20 mg/kg, p.o.}
`blockedicv. CRF-induced
`
`colonic motility
`
`
`Tetrahydrotetraazaacenaphthylenes Neurocrine=Tri 12t 268545-87-5 Ky=4 791 622 5.27 3.72 4174 290 - - - - Reduced footshock oriv, [104,105]
`
`
`
`
`
`
`
`
`
`
`
`
`
` (NBI34041) CRF-induced ACTH (3 mg/kg)
`
`Hexa- and
`GSK
`Tri
`2ba
`862901-68-6
`IC59=14
`6.78
`682
`6.25
`433
`4845 34.0 33
`10
`-
`-
`@/P = 1.3; MED = 30 mg/kg
`[106]
`tetrahydrotetraazaacenaphthylenes .inrat pup ultrasonic
`
`
`vocalization model
`
`
`Tetrahydrotetraazaacenaphthylenes
`GSK
`Tri
`3a
`476645-12-2
` ICs5g=100 986
`849
`6.15
`5.99
`483.5 21.1
`71
`8
`25
`53
`-
`[107]
`
`Cyclopental[d|pyrimidines
`GSK
`Bi
`3ac
`474655-90-8
`ICs9=174 7.19 64
`5.99
`3.90
`390.3 29.0 22
`4
`5.4
`3.1
`B/P =035
`7]
`Dihydropyrrolo[2,3-dlpyrimidines
`GSK
`Bi
`4fi
`474657-07-3
`ICso=48
`1.84
`3.53
`3.53
`3.30
`414.2 468 86
`9
`3.3
`6
`B/P = 2.30; EDsp = 2.0 mg/kg
`7]
`.inrat pup ultrasonic
`
`vocalization model
`‘Top’ heteroaryl-substituted
`GSK
`Bi
`Za
`474655-69-1
` IC5g=32
`0.79
`6.04
`6.04
`6.01
`496.4 88.0 52
`12
`37
`5.1
`B/P = 2.30; EDsp = 10.0 mg/kg
`[108]
`
`dihydropyrrolo[2,3-dlpyrimidines p.o.inrat pup ultrasonic
`
`vocalization model
`
`‘Top’ heteroaryl-substituted
`GSK
`Bi
`27
`727992-91-8
`ICs9=35
`3.93
`3.07
`3.07
`1,23
`439.5 843 -
`-
`-
`-
`-
`[92]
`
`dihydropyrralo[2,3-d]pyridines
`‘Top’ heteroaryl-substituted
`GSK
`Bi
`3
`786701-83-5
` IC39=66
`4.81
`1.54
`1,54
`0.79
`4024 75.5 66
`19
`24
`16
`G/P = 3.7; reduced icv.
`[95]
`dihydropyrralo[2,3-d]pyridines
`(GW876008)
`CRF-induced gerbil forepaw
`treading (10 mg/kg), marmoset
`defensive postures (10 mg/kg),
`rat pup ultrasonic vocalization
`
`(30 mg/kg)
`
`Indanylpyrazines
`Pfizer
`Mono 19
`675198-68-2. Ky=11
`146
`385
`3.85
`365
`436.5 69.2 -
`-
`-
`-
`-
`[109]
`2-Aryloxy-alkylaminopyridines
`Pfizer
`Mono 2
`175139-41-0
`ICs5g=7
`563
`620
`6.18
`3.73
`3275 31.4 3.6 (fasted),
`4]
`11
`83
`Reduced iv. CRF-induced
`[96]
`(CP-316311)
`37 (fed)
`ACTH (10 mg/kg), defensive
`withdrawal (10 mg/kg),
`fear-potentiated startle
`(32 mg/kg, p.o.)
`[97]
`Reduced iv. CRF-induced
`88
`53
`17
`326.5 34.2 22(fasted),
`483
`69
`733
`7.23
`[Csp=5
`175140-00-8
`Mono 3a
`Pfizer
`2-Aryloxy-4-alkylaminopyridines
`ACTHandfear-potentiated
`64 (fed)
`startle (10 mg/kg, p.0.)
`
`
`
`
`
`OLOZAQW01/6AquINN‘S|BUN|OA.AepoyAleaodsiqbrig
`
`SM3IAId
`
`
`Reviews + POST SCREEN
`
`
`
`
`
`SZEwor'Aepoy{ueacos|pErupmam
`
`5
`
`

`

`TABLE 1 (Continued)
`
`N33YDS LSOd + smalnay
`
`
`SMalAIY
`
`57
`
`35
`
`1.18
`
`3.52
`
`3.68
`
`6.66
`
`444321-96-4
`
`7b
`
`Bi
`
`BMS
`
`BMS
`
`Mono
`
`7F
`
`777940-17-7
`
`Ky=52
`
`2.53
`
`686
`
`6.22
`
`394.5
`
`674
`
`35
`
`52
`
`25
`
`5.1
`
`[113]
`
`CAS
`Core Best
`Oral
`CRF,
`Company
`Refs
`tya (h) Notes
`CGplasma
`Vy
`Clog P clog Do-7 Clog Dpy-2 MW
`ry
`cycles exemplars_registry
`affinity
`bioavailability (ml/min kg) (L/kg)
`(nw)
`(F%)
`414
`32
`Ka=42
`
`
`[110]
`B/P = 0.21; anxiolytic-like
`7-Aryl-6,7-dihydroimidazoimidazole
`activity in mouse canopy
`
`madel (32 mg/kg)
`51
`BMS
`Tri
`8e
`7.93
`468.6 25.5 35
`06
`444323-42-6 Ky=23
`
`B/P=0.3 1111]
`Imidazo[1,2a]benzimidazoles
`7.14
`BMS
`Tri
`8.45
`4516
`384
`52
`05
`9d
`444324305
`Ky=78
`B-Aryl-1,3a,7,8-tetraaza-
`Anxiolytic-like activity in
`[112]
`cyclopenta[a]indenes
`mouse canopy model
`(30 mg/kg)
`-
`
`2-Anilno-3-phenylsulfonyl-
`6methylpyridines
`798
`399.5
`0.63
`3.09
`3.10
`795300-31-1
`2a
`Bi
`BMS
`[91]
`-
`[C59 = 0.8
`
`Dihydropyridopyrazinones
`BMS
`Bi
`3.69
`3.69
`1.48
`386.5 756
`492
`2d
`937723-70-1
`- [91]
`
`Iso = 10
`Dihydropteridines
`V7
`MTIP
`910551-43-8 K,=022 3.96
`3.55
`3.55
`1.64
`420.0 838 91
`49
`39
`Reduced conflict behavior;
`[54,55]
`Imidazo[1,2b]pyradizine
`Eli Lilly/
`Bi
`NIAAA
`reduced ‘hangover’ anxiety-like
`behavior in elevated plus-maze
`(10 mg/kg); reduced ethanol
`self-administration (10 mg/kg);
`reduced ethanol-seeking
`behavior in ethanol post-
`dependent oralcohol-
`preferring rats
`MPZP
`202579-76-8
`5.32
`2.95
`2.93
`0.50
`398.5 61.1
`-
`Ky=49
`Pyrazolo[1,5a]pyrimidine
`Scripps
`Bi
`Reduced defensive burying
`[52,53,56,57]
`behavior; reduced ethanol,
`(Dupont/BMS
`nicotine and cocaine
`composition
`self-administration in
`patent)
`dependence models
`13-15
`459856-18-9
`2.99
`2.94
`2.94
`1.66
`3404 77.2 40
`179
`149
`13.5
`BMS
`Bi
`Ka =6.1
`
`
`
`8-(Pyrid-3-y)pyrazolo[1,5a]-1,HPyidSyDpyrazolo[sa-l,~~-=&BMS~«&BL”S*C*SX1S~*«SORSIBD~Ky=6l299294«204°+4466~”~éA77240...478149135Amdolyticlikeactivityin.198)
`Pexacerfont
`3,5-triazines
`elevated plus-maze and
`defensive withdrawal
`(BMS-562,086)
`models (10 mg/kg, p.o.);
`observed log P = 4.32;
`solubility of 16 g/mlin
`water (pH 7.4) and
`16.3 mg/mlin 0.01 N HCl
`(pH 25); good
`pharmacokinetics in
`nonhuman primates
`Anniolytic-like activity in
`elevated plus-maze and
`defensive withdrawal
`models (10 mg/kg, p.o.);
`observed log P = 4.76;
`solubility < 1 g/ml in water
`(pH 7.4) and 2.5 mg/mlin
`
`0.01 N HCl (pH 2.5); inferior
`oral pharmacokinetics in
`chimpanzee compared with
`Pexacerfont
`
`
`
`worfepoyueaoos|phrupamn9/€
`
`
`
`8-(4-Methoxypheny|)pyrazolo
`[1,5q]-1,3,5-triazines:
`
`BMS
`
`Bi
`
`6 in 1st 12-3
`in 2™4
`(BMS-561,388)
`
`202578-88-9
`(free base)
`
`Kg=47
`
`6.63
`
`2.15
`
`1.99
`
`035
`
`399.5 74.0 51
`
`20
`
`146
`
`97
`
`[98,114]
`
`Abbreviations: ACTH, adrenocorticotropic hormone;B/P, brain/plasmaratio; c log P, calculated log P; c log D, calculated log D at specified pH; CRF, corticotropin-releasing factor; MW, molecular weight; NIAAA, NationalInstitute on Alcohol Abuse
`and Alcoholism; pK,, negative log of the acid-dissociation constant; PSA, polar surface area.
`? Intravenous pharmacokinetic parameters include C; (clearance from plasma), Vg (volumeofdistribution at steady state) and f),2 (plasmahalf-life). Physiochemical properties were calculated using Advanced Chemistry Development (ACD/Labs)
`Software v. 8.19 for Solaris.
`
`
`
`
`
`
`
`
`
`OLOZAeW+01/6eQUINN‘S|auuN|oA.AepolAl@aoosiqBrug
`
`6
`
`

`

`mam
`
`
`
`
`
`
`
`
`
`Phase I/ll
`
`Nov 2005
`
`Completed
`
`PhaseII
`
`Dec 2006
`
`Completed
`
`Escitalopram NCTO0135421
`
`-
`
`NCT00399438
`
`Reviews + POST SCREEN
`
`SM3IAId
`
`
`
`LLEworfhepoy{ueac2s|pGrup
`
`TABLE 2
`Recentclinical trials for CRF, antagonists
`Company
`Compound
`Stage
`Date
`Current status Trial description
`Reference
`_—Clinicaltrials.gov or other identifier
`initiated
`compound
`
`GlaxoSmithKline/
`GW876008
`Phase |
`Nov 2006
`Completed
`Metabolism in smokers versus nonsmokers
`-
`NCT00429728
`Neurocrine
`
`GSK561679 and
`GW876008
`GW876008
`GW876008
`GW876008
`
`Phase I/lla_ Nov 2006
`
`fMRIof regional cerebral blood flow in IBS patients
`
`-
`
`NCT00376896
`
`Phase I/lla_ Aug 2007
`Phase Ila
`Dec 2006
`Phase II
`Nov 2006
`
`Terminated
`Completed
`Completed
`
`
`
`
`
`-
`-
`-
`
`NCT00511563
`NCT00385099
`NCT00421707
`
`PhaseII
`
`Nov 2006
`
`Completed
`
`Paroxetine
`
`NCT00397722
`
`
`
`
`
`OLOZAQW01/6AquINN‘S|BUN|OA.AepoyAleaodsiqbrig
`
`NCT00423761
`-
`Safety study; potential interaction with midazolam
`Completed
`Dec 2006
`Phase |
`GW876008
`NCT00424697
`Lorazepam
`fMRI of emotional processing in healthy volunteers
`Completed
`Mar 2007.
`Phase|
`GW876008
`NCT00508911
`-
`Effects on pharmacokinetics of oral contraceptives
`Terminated
`Jun 2007.
`Phase|
`GW876008
`
`
`
`
`
`GSK561579 Alprazolam=NCT00426608Phase| Oct 2006 Completed Effects on metyrapone-induced ACTHsecretion
`GSK561579
`Phase|
`Oct 2007
`Completed
`Variability in absorption study
`-
`NCT00539136
`GSK561579
`Phase|
`Sep 2007
`—_—Recruiting
`fMRI of emotional processing in healthy volunteers
`Lorazepam
`NCT00513565
`April 2009
`Completed
`
`GSK561679 Oct 2008~—-PhaseIl Recruiting Multi-site, double-blind, placebo-controlled study in - NCT00733980
`
`Endocrine responses to meals in IBS patients
`Gut blood flow and pain sensitivity in IBS patients
`Multi-site, double-blind, placebo-controlled study in
`IBS patients
`GSK561679 and fMRI response to public speaking in social anxiety disorder Alprazolam=NCT00555139PhaseI/lla Mar 2007 Completed
`
`GW876008
`GW876008
`
`Multi-site, double-blind, placebo-controlled study in
`social anxiety disorder
`
`
`major depression
`GSK586529
`Phase|
`-
`Completed
`Single-dose, escalating trial toward anxiety and
`-
`www.neurocrine.com/ 3rd quarter,
`depression indications
`2008 release
`
`BMS
`Pexacerfont
`PhaseII/IIl_
`Jul 2007
`Completed
`Multi-site, double-blind, placebo-controlled study in
`Escitalopram NCT00481325
`(BMS-562,086)
`generalized anxiety disorder
`Pexacerfont
`Multi-site, double-blind, placebo-controlled study in
`(BMS-562,086)
`major depression
`Pexacerfont
`Multi-site, double-blind, placebo-controlled study in
`(BMS-562,086)
`IBS patients
`BMS-561,388
`Phase|
`2003-2004 Uncertain
`Effects on reproductive hormones and menstrualcycle in
`-
`http://myprofile.cos.com/miss_kc02
`
` young healthy women
`Pfizer
`CP-316,311
`Phase II
`Apr 2005
`Terminated Mar Multi-site, double-blind, placebo-controlled study in
`Sertraline
`NCT00143091
`2006 (negative
`major depression
`results)
`PF-57,2778
`Phase|
`-
`Terminated
`Safety study toward generalized anxiety disorder indication
`-
`-
`
`Ono
`ONO-2333Ms
`PhaseII
`Jun 2007
`Terminated Jul
`Multi-site, double-blind, placebo-controlled study in
`-
`NCT00514865
`2008 (negative—_recurrent major depression
`results)
`
`
`
`
`
`Taisho/Janssen Dec 2004=UncertainTAI-041/ Phase| - - -
`
`
`Gohnson&Johnson)
`JNJ-19567470
`
`Sanofi-Aventis
`SSR 125543
`Phase|
`-
`Uncertain
`-
`-
`http://en.sanofi-aventis.com/research_
`innovation/rd_strategy/cns/cns.asp
`(Feb 2008)
`
`Neurocrine
`NBI-34101
`Phase|
`-
`-
`-
`-
`-
`
`
`NIH [115] Antalarmin Preclinical —- - Completed pre-PhaseI toxicity studies -
`
`
`
`
`
`
`
`7
`
`

`

`Reviews*POST
`
`SCREEN
`
`8
`
`

`

`o)aA
`a)
`ES
`a)
`
`acc
`
`) af
`
`27]7]
`
`