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None described

  • Chemotherapy-induced nausea & emesis; "Irritable bowel syndrome; inflammatory bowel disease; +Chronic obstructive pulmonary disorder; #No further development activity reported
  • Chemotherapy-induced nausea & emesis; "Irritable bowel syndrome; inflammatory bowel disease; +Chronic obstructive pulmonary disorder; #No further development activity reported

NK Receptor Antagonists - The mammalian tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) bind and activate NK receptors with SP preferring NK1, NKA preferring NK2 and NKB preferring the NK3 receptor. Preclinical findings suggest utility of tachykinin receptor antagonists in diverse disorders including chemotherapy-induced emesis, anxiety and depression, migraine, pain, IBD, micturition disorder and asthma. Accordingly, a considerable effort has identified an impressive variety of subtvDe selective and non-selective tachykinin receptor antagonists (2). New preclinical and clinical studies with a subset of the available tachykinin receptor antagonists have significantly contributed to clarifying the therapeutic utility of tachykinin receptor antagonists. Further, several useful small molecule antagonists have been described recently.

A milestone accomplishment in o \ tachykinin research was the U.S. registration V-\ of the NK1 antagonist, aprepitant, for treating h2n )—\ chemotherapy-induced nausea and emesis (2). Recent clinical studies showed that aprepitant monotherapy is less effective than the 5-HT3 antagonist, ondansetron, in preventing acute emesis but more effective in reducing delayed emesis (16). Aprepitant, in combination with ondansetron and dexamethasone, provided superior relief from both acute and delayed emesis. The centrally-acting NK1 antagonist, CP-122,721, reduced post-operative nausea and emesis when used in combination with ondansetron (2, 17). Other centrally-acting NK1 antagonists include 1 (SSR240600), which shows high affinity (Ki = 0.006 nM) for the human NK1 receptor (18).

Efforts to advance NK1 antagonists for anxiety and depression continue, but have been complicated by the characteristic high failure rate of depression trials. Although the initial depression trial reported that aprepitant and paroxetine had similar efficacy, a follow up dose-finding study failed to differentiate either agent from placebo. Similar results were found for a backup compound with similar potency and brain penetration (19). The available data suggest that NK1 antagonist therapy requires a similar time to onset of action versus SSRIs, athough the reported low incidence of sexual side-effects with NK1 antagonists represents a potential advantage.

PET studies with aprepitant and [18F]-SPA-RQ, a brain penetrant, selective, and highly potent (K = 0.04 nM) ligand, have demonstrated that high levels of NK1 receptor occupancy (>90%) were associated with significant antidepressant and antiemetic effects, whereas lower receptor occupancy was associated with reduced efficacy (20). These studies have also established that high levels of central NK1 receptor occupancy were achieved with aprepitant in earlier negative clinical trials for pain. A non-CNS penetrant NK1 antagonist, nolpitanium besilate (SR-140,333), is under investigation for several indications, including IBD and food allergy (2, 21).

New studies have further defined the therapeutic potential of NK2 receptor antagonists. In asthmatics, the NK2 antagonist, saredutant, was Ineffective in reducing airway hyper-responsiveness to adenosine, while producing no benefit with respect to airway function (2, 22). Interestingly, preclinical studies suggest utility of saredutant in anxiety and depression (23, 24). Further new data support the presence of NK2 receptors in both rodent and human brain (25, 26).

Additional NK2 receptor antagonists include nepadutant, presently pursued as a possible treatment for IBS and asthma. This compound was shown clinically to inhibit NKA-stimulated, but not basal, gastrointestinal motility (2, 27). Furthermore, oral doses of nepadutant have reduced diarrhea induced by bacterial toxins in mice, acetic acid irritation-induced motility in rats, and acetic acid-induced rectocolitis in guinea pigs (28, 29).

Dual NK1/NK2 receptor antagonists continue to be of interest, especially for respiratory diseases. Compound 2 (DNK-333), a potent dual antagonist (NK1/2 IC5o

= 4.8/5.5 nM) reduced NKA-induced bronchoconstriction in asthmatics following oral administration (3, 30). A new antagonist, 3 (SCH-206272), displays similar potency across NK1, NK2 and NK3 receptors with K( = 1.3, 0.4, 0.3 nM, respectively (31 ).

Regarding the therapeutic utility of NK3 receptor antagonists, osanetant displayed antipsychotic activity in a recent clinical trial, in accord with preclinical data suggesting that central NK3 receptor blockade modulates dopaminergic, noradrenergic and serotonergic activity (2, 32-35). Furthermore, immunohisto-chemical studies demonstrated the presence of NK3 receptors in human brain regions associated with schizophrenia (36, 37).

Another clinically useful NK3 antagonist, talnetant, may define further the therapeutic utility of NK3 antagonists in a variety of indications (2). New talnetant analogs could be useful pharmacological tools: 4 (SB-222200) with a K, of 4.4 nM, achieved enhanced brain penetration, while 5 (SB-235375), with a K, of 2.2 nM, displayed reduced CNS exposure (38, 39). New dual NK2/NK3 receptor antagonists include 6 (SB-400238), with NK2 Kj= 0.8 nM, and NK3 K = 0.8 nM (40).

CRF Receptor Antagonists - CRF and CRF receptors play a key role in mediating in the body's response to stress, and as such, have provided compelling targets for novel pharmacological approaches to depression, anxiety, and stress disorders (7, 41). Major industry efforts have identified potent and selective antagonists for the CRF1 receptor, as summarized in recent reviews (4, 7, 41, 42).

Since the report of antidepressant activity with R121919 in an open-label, Phase 2 trial in depressed patients, no new clinical results with CRF1 antagonists have been published (7). However, advances in CRF neurobiology have further validated this target, including a strengthening of CRF's role in a primate model of depression and demonstrations of CRF interactions with known brain sites of action of antidepressants and anxiolytics such as the dorsal raphe and amygdala (43-45). In addition, preclinical studies expanded the profiles of key CRF1 antagonists in Table 1 (6, 8, 46-52). Findings gleaned from these studies which are relevant to drug discovery efforts include the following: (a) Consistent in vivo actions of acute CRF1 antagonists include attenuating the behavioral effects of icv CRF administration, and blunting HPA axis stimulation produced by stress or peripherally-administered CRF. (b) Efficacy of CRF1 antagonists in selected anxiolytic, antidepressant, antistress assays has been reported, though there are inconsistencies in outcomes across laboratories which may relate to experimental factors such as levels of stress, strain/species used, etc. (c) Ex vivo receptor binding

techniques have estimated CRF1 occupancy in rat cortex ranging from 50% to 85% at efficacious doses (51, 52). (d) Chronic dosing studies report sustained efficacy, but a tolerance to the acute effects of stress on the HPA axis, suggesting that chronic CRF1 antagonism may not adversely affect HPA axis (46, 53).

Preclinical studies provided further support for the utility of CRF1 antagonists in other therapeutic indications. These include stress-related gastrointestinal disorders (IBS, gastric ulceration), stroke, drug addiction, and inflammatory disorders (54-59).

A topological description summarized drug design strategies for identifying potent, non-peptidic CRF1 antagonists (7). New analogs have resulted from a systematic effort aimed at conformationally constraining the top side-chain of known bicyclic templates. The tricyclic compound 7 is a representative example of this large class of structures (60). Chemical structures, such as 8-10, which are beginning to diverge from the classical CRF1 receptor antagonist pharmacophore, have also emerged recently from the patent literature (61-63). The biological activities of these compounds have not been disclosed.

Progress has been reported in developing non-peptidic CRF1 radioligands (64, 65). In vitro, [3H]-SN003 reveals specific CRF1 binding in rat brain tissues, which was consistent with known CRF1 receptor distributions (65).

NPY Receptor Antagonists - Since its discovery as a highly potent feeding stimulant, NPY has been considered an attractive target for the treatment of obesity. Pharmacological studies suggested that, among the six characterized NPY GPCR subtypes, the hypothalamic Y1 and Y5 receptors most likely played a critical role in the NPY regulation of appetite, food intake, and energy expenditure. However, experiments with genetic models have been inconclusive in this regard (66-70).

In the last year, several reports have challenged the importance of the Y5 receptor in NPY-induced feeding. The imidazole H (FR252384) is a potent (Ki = 2.3 nM), orally active, and CNS penetrant Y5 antagonist, but its levels in the brain poorly correlated with reductions in food intake (11).

Another imidazole, 12 (Kt = 1.2 nM) was orally active in blocking the orexigenic effect of a selective Y5 agonist (bPP) injected icv In rats. Again, despite achieving adequate plasma, CNS, and CSF exposure, 12 failed to demonstrate efficacy in natural feeding models (71). Similarly, the selective Y5 antagonists 13 and 14 (IC50 = 26 and 3.5 nM, respectively) prevented or attenuated bPP-induced feeding in rats, but remained ineffective in inhibiting the orexigenic effect of NPY (72, 73). The carbazole 15 (NPY5RA-972) is another potent (IC50 = 3 nM) and highly selective Y5 antagonist. When administered orally to rats, its plasma, brain and CSF concentrations largely exceeded its ICso- While 15 blocked the feeding behavior elicited by icv injection of a selective peptidic Y5 agonist, it did not affect spontaneous feeding or fasting-induced feeding in rats (12,13).

The specificity of the anorectic effect of CGP 71683A, known as the first potent (IC50 = 2.9 nM), non-peptidic Y5 antagonist to be disclosed, was recently challenged, considering its newly uncovered affinity at a2-adrenergic and muscarinic receptors, at the serotonin reuptake site, and its dose-related inflammatory side-effect in animals (74). Other Y5 antagonists reduced food consumption in a fasting-induced feeding model in rats, but the specificity of these effects is unclear (75, 76).

In contrast to the abundance of Y5 antagonists, only a few potent, selective, orally bioavailable, and brain penetrant Y1 antagonists have been characterized to date, though these agents encompass diverse chemical classes (77). The evidence pointing to an important role of the Y1 receptor in the regulation of food intake has been reviewed recently (77). J-115814, a potent (hY1 K, = 1.4 nM), and selective Y1 antagonist, partially inhibited (- 50%) icv NPY-induced food intake in satiated rats, and suppressed physiological feeding in lean and obese, but not in Y1 -/- mice. The incomplete inhibition of NPY-induced feeding is consistent with the extent of feeding suppression observed in Y1 -/-, suggesting an important, albeit not exclusive, role of the Y1 receptor in the orexigenic properties of NPY (9).

The lack of a pharmacokinetic/pharmacodynamic relationship with many selective Y5 antagonists, coupled with their inability to block the orexigenic effect of NPY in rats, and the finding that there was no reduction of NPY-induced feeding in Y5 -/- mice, have recently challenged the notion that the Y5 receptor is the NPY "feeding receptor" (78). While the Y1 receptor can still be considered an attractive drug target, additional receptor subtypes may need to be invoked to fully explain the neurobiology of NPY in the context of obesity. Interestingly, Y1 antagonists, attenuated the orexigenic action of MCH by 70%, suggesting a strong interrelationship between these two hypothalamic systems (79).

MCH Receptor Antagonists - The mammalian cyclic nondecapeptide MCH only recently emerged as a neuropeptide importantly related to feeding behavior, energy expenditure and the control of obesity. Reviews on MCH biology have appeared recently (80-82). This section will discuss compelling animal gene deletion and transgenic overexpression data documenting a key role of the MCH system in food intake and energy expenditure, and data from the initial discovery of small molecule MCHR1 antagonists.

The MCH peptide was discovered over 20 years ago as a systemicaliy released pituitary factor that concentrated melanin granules in melanophores located in scales of teleost fish, resulting in a refractory index change in the fish scale so that it appeared lighter in color (83). It was later found that the mammalian peptide paralogue was restrictively expressed in lateral hypothalamic area neurons with widespread axonal projections, particularly to brain regions involved in appetite control, energy balance, olfaction, food searching behavior, arousal and anxiety, and swallowing and mastication (84). Despite the historical understanding of the role of the lateral hypothalamic area in food intake and energy expenditure, a role for MCH in ingestive behavior was only recognized less than ten years ago based on initial work with the peptide and its mRNA. Expression of the MCH gene was increased two- to three-fold in hypothalami of ob/ob mice (85). In these studies preproMCH mRNA levels also increased with fasting, in both normal and ob/ob animals. ICV administration of MCH in rats led to an immediate, two- to three-fold increase in food intake. Also, targeted deletion of the MCH gene resulted in mice that had reduced body weight and increased energy expenditure (86). Consistent with this, the generation of transgenic mice that had a two-fold increase in the steady-state levels of preproMCH RNA levels within the same lateral hypothalamic area neurons resulted in animals that displayed diet-induced obesity, hyperphagia and insulin resistance, characteristics indicative of the obesity/diabetic phenotype in man (87).

The first MCH receptor was originally identified as an orphan G-protein coupled receptor, termed SLC-1(88). Efforts in the late 1990's to "deorphanize" the various putative G-protein coupled receptors yielded the MCHR1 as one of the success stories (89, 90). The MCHR1 binds to and is activated by nanomolar to subnanomolar MCH concentrations, and stimulates pertussis toxin-sensitive decreases in cAMP, inositol phosphate turnover, intracellular calcium mobilization, and stimulation of MAP kinase activity, consistent with coupling to multiple G-proteins including G0i, Gao, and Gaq (91). MCHR1 mRNA and protein are expressed in the same areas as the terminal fields of the lateral hypothalamic area MCH neurons (89, 90, 92). Paralogues of this MCHR1 gene are expressed in all mammalian species examined to date.

A second human MCH receptor (MCHR2) was recently identified in genomic databases and functional expression studies, and displays 32% identity to the human MCHR1 (93-95). The MCHR2 binds to and is activated by nanomolar to subnanomolar MCH concentrations, and activates inositol phosphate metabolism in a pertussis toxin insensitive manner, consistent with coupling to Gaq. The MCHR2 is expressed in essentially the same CNS regions as MCHR1, though mRNA levels in the hypothalamus appear to be substantially lower than MCHR1. It is of interest that several mammalian species do not express MCHR2 or express a pseudogene, including rat, mouse, hamster, guinea pig or rabbit, while the MCHR2 is functionally expressed in canine, ferret, rhesus, macaque and man (95).

Two groups have independently generated homozygous null MCHR1 mice and the mice display hyperphagia, hypermetabolism and are resistant to diet-induced obesity (96, 97). These results clearly establish MCHR1 as a mediator of MCH effects on energy homeostasis and food intake in mice.

The first small molecule antagonist of the human MCHR1, 16 (SNAP-7941), inhibits MCH-mediated calcium responses and inositol phosphate accumulation in transfected cells (pA2 = 9.24), in a manner consistent with competitive inhibition (14). [3H]-SNAP-7941 was used in autoradiographic studies to map the location of the binding sites in rat brain (in the presence of unlabelled prazosin and dopamine), and displayed a similar localization to that of both MCHR1 mRNA and protein (89, 90, 92). Compound 16 binds to the human MCHR1 (Kd = 0.18 nM). Although not orally bioavailable, it antagonized MCH-stimulated palatable food intake and body weight gain in rats via ip injection. Moreover, 16 decreased body weight and food intake in a rat model of diet-induced obesity. Finally, 16 displayed antidepressant and anxiolytic properties in the rat forced swim test, in a maternal separation test in guinea pigs, and in a rat social interaction test. These results support additional utility of MCHR1 antagonists in anxiety and depression, consistent with MCHR1 brain localization.

Compound 17 (T-226296) is an orally ■(CH3>2 active and selective MCHR1 competitive antagonist (15). It inhibited MCH binding (IC5o = 5.5 nM), reversed MCH-mediated inhibition of forskolin-stimulated cAMP accumulation, and blocked MCH-mediated intracellular calcium mobilization and arachidonic acid release, respectively. In the latter assay, 17 appeared to be a competitive antagonist. After oral dosing (30 mpk), 17 reduced icv MCH-stimulated food intake by approximately 90%.

Conclusions - Over the past decade, significant progress has been made identifying and advancing non-peptidic neuropeptide receptor antagonists, with a major success achieved in bringing an NK1 antagonist to registration. Recent animal genetic models point to the potential validity of several neuropeptide receptors as targets for drug discovery, though the need for safe, efficacious compounds cannot be underestimated. Many of the molecular targets discussed, despite being at different levels of maturity, have the potential to be future success stories.


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