John F McElroy

Bristol-Myers Squibb, New York City, New York, United States

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Publications (15)59.37 Total impact

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    ABSTRACT: This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. These CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 6.1 +/- 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.
    Journal of Medicinal Chemistry 05/2009; 52(9):3084-92. · 5.61 Impact Factor
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    ABSTRACT: This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 4.7 +/- 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.
    Journal of Medicinal Chemistry 05/2009; 52(9):3073-83. · 5.61 Impact Factor
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    ABSTRACT: Several studies have suggested that neurokinin-1 (NK1) receptor antagonists may have therapeutic potential as novel antidepressant drugs. To test these compounds preclinically, gerbils have become one of the preferred species in that they demonstrate close NK1 receptor homology with humans and bind NK1 antagonists with higher affinity than rats and mice. The intent of the present study was to determine whether the forced-swim test (FST), one of the most commonly used animal tests of antidepressant-like activity, could be adapted for use with the gerbil. Critical factors in the establishment of this assay included swim tank diameter, weight, and sex of the animals tested. Pharmacological validation of the FST using standard antidepressant compounds (eg fluoxetine, paroxetine, desipramine) resulted in decreased immobility time during the test, indicative of an antidepressant-like effect. Similar to results reported for the rat and mouse FST, the antipsychotic drug haloperidol increased immobility, whereas the psychostimulant, amphetamine decreased immobility, and anxiolytic drugs (eg buspirone) had no effect. Investigation into the locomotor effects of all compounds tested was consistent with previous reports in other species, with the exception of paroxetine, which produced hyperactivity at therapeutically effective doses in gerbils. In addition to standard antidepressants, NK1 antagonists (L-733060, MK-869, and CP-122721) all reduced immobility in the gerbil FST without affecting locomotor activity. Overall, these results suggest that the gerbil is an ideal species for use in the FST, and that this paradigm may have predictive validity for identifying novel antidepressant compounds.
    Neuropsychopharmacology 08/2008; 33(8):1919-28. · 8.68 Impact Factor
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    ABSTRACT: Amitriptyline and gabapentin are the primary treatments for painful diabetic neuropathy (PDN), and it is clear that they produce beneficial effects, but there are questions about these treatments that have not been adequately addressed. For example, although there is a growing consensus that the therapeutic effects of amitriptyline in pain patients are independent of its effects on mood, it is not clear that amitriptyline has specific and direct effects on pain. There is also a fairly broad consensus that gabapentin is safe and well tolerated, but the side-effect profile of gabapentin has not been adequately assessed in pain populations. The rat streptozotocin (STZ) model of PDN was used (a) to assess the effects of amitriptyline on objective, quantitative measures of tactile allodynia, a common type of pain in PDN patients, and (b) to assess the side effects of gabapentin using measures of motor/ambulatory and cognitive function. Amitriptyline did not attenuate STZ-induced mechanical allodynia, even after chronic administration of high doses. Gabapentin produced robust anti-allodynic effects but also produced deficits in tests of motor/ambulatory and cognitive functions. The present experiments suggest that the beneficial effects of amitriptyline in PDN may not be a result of anti-allodynic efficacy and that gabapentin produces robust anti-allodynic effects but may also produce significant motor and cognitive deficits even at or near the lowest effective doses. These findings challenge the consensus opinions about these primary treatments for PDN and suggest that their therapeutic and adverse effects should be explored further in pain patients.
    Experimental and Clinical Psychopharmacology 03/2006; 14(1):42-51. · 2.55 Impact Factor
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    ABSTRACT: Benzodiazepines continue to be widely used for the treatment of anxiety, but it is well known that benzodiazepines have undesirable side effects, including sedation, ataxia, cognitive deficits and the risk of addiction and abuse. CRF(1) receptor antagonists are being developed as potential novel anxiolytics, but while CRF(1) receptor antagonists seem to have a better side-effect profile than benzodiazepines with respect to sedation and ataxia, the effects of CRF(1) receptor antagonists on cognitive function have not been well characterized. It is somewhat surprising that the potential cognitive effects of CRF(1) receptor antagonists have not been more fully characterized since there is some evidence to suggest that these compounds may impair cognitive function. The Morris water maze and the delayed non-matching to position test are sensitive tests of a range of cognitive functions, including spatial learning, attention and short-term memory, so the objective of the present experiments was to assess the effects of benzodiazepines and CRF(1) receptor antagonists in these tests. The benzodiazepines chlordiazepoxide and alprazolam disrupted performance in the Morris water maze and delayed non-matching to position at doses close to their therapeutic, anxiolytic doses. In contrast, the CRF(1) receptor antagonists DMP-904 and DMP-696 produced little or no impairment in the Morris water maze or delayed non-matching to position test even at doses 10-fold higher than were necessary to produce anxiolytic effects. The results of the present experiments suggest that, with respect to their effects on cognitive functions, CRF(1) receptor antagonists seem to have a wider therapeutic index than benzodiazepines.
    Psychopharmacology 05/2005; 178(4):410-9. · 4.06 Impact Factor
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    ABSTRACT: CRF(1) antagonists DMP696 and DMP904 were designed as drug development candidates for the treatment of anxiety and depression. Both compounds display nanomolar affinity for human CRF(1) receptors, and exhibit >1000-fold selectivity for CRF(1) over CRF(2) receptors and over a broad panel of other proteins. DMP696 and DMP904 block CRF-stimulated adenylyl cyclase activity in cortical homogenates and cell-lines expressing CRF(1) receptors. Both compounds inhibit CRF-stimulated ACTH release from rat pituitary corticotropes. Binding and functional studies indicate that DMP696 and DMP904 behave as noncompetitive full antagonists. DMP696 and DMP904 exhibit anxiolytic-like efficacy in several rat anxiety models. In the defensive withdrawal test, both compounds reduce exit latency with lowest effective doses of 3 and 1 mg/kg, respectively. The anxiolytic-like effect is maintained over 14 days of repeated dosing. In the context of a novel environment used in this test, DMP696 and DMP904 reverse mild stress-induced increases in plasma CORT secretion but at doses 3-4-fold greater than those required for anxiolyticlike efficacy. DMP696 and DMP904 are ineffective in three depression models including the learned helplessness paradigm at doses up to 30 mg/kg. At lowest anxiolytic-like doses, DMP696 and DMP904 occupy >50% CRF(1) receptors in the brain. The in vivo IC(50) values (plasma concentrations required for occupying 50% CRF(1) receptors) estimated based upon free, but not total, plasma concentrations are an excellent correlation with the in vitro IC(50) values. Neither compound produces sedation, ataxia, chlordiazepoxide-like subjective effects or adverse effects on cognition at doses 10-fold higher than anxiolytic-like doses. Neither compound produces physiologically significant changes in cardiovascular, respiratory, gastrointestinal or renal functions at anxiolytic-like doses. DMP696 and DMP904 have favorable pharmacokinetic profiles with good oral bioavailabilities. The overall pharmacological properties suggest that both compounds may be effective anxiolytics with low behavioral side effect liabilities.
    CNS Drug Reviews 01/2005; 11(1):21-52. · 4.92 Impact Factor
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    ABSTRACT: Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.
    Journal of Medicinal Chemistry 12/2004; 47(23):5783-90. · 5.61 Impact Factor
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    ABSTRACT: The selective dopamine D3 receptor ligand 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) produced stereotypical sniffing and climbing, increased locomotor activity, and caused 6-hydroxydopamine-lesioned animals to rotate in a contralateral direction, behavioral effects highly predictive of dopamine agonist activity. In contrast, 7-OH-DPAT was inactive in the conditioned avoidance response, catalepsy, and anti-apomorphine test, animal models highly predictive of dopamine antagonist activity. These results indicate that 7-OH-DPAT is an agonist at dopamine receptors in vivo. © 1993 wiley-Liss, Inc.
    Drug Development Research 10/2004; 30(4):257 - 259. · 0.87 Impact Factor
  • John F. McElroy, Kathryn A. Ward
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    ABSTRACT: The purpose of the present study was to characterize the rotational behavior in unilateral 6-OHDA-lesioned rats produced by the high affinity and selective dopamine D3 receptor ligand 7-OH-DPAT. Qualitatively similar to the direct-acting DA agonist apomorphine, 7-OH-DPAT causes rats to rotate in a direction contralateral to the side of the nigrostriatal DA pathway lesion. This effect is dose-dependent and the minimum effective dose is 0.03 mg (0.12 m̈mol)/kg. 7-OH-DPAT-induced rotation is blocked in a dose-dependent manner by oral pretreatment with the “D2-like” receptor antagonists haloperidol, eticlopride, or clozapine, but not by the “D1-like” antagonist SCH 23390. The rank order potency for inhibition of 7-OH-DPAT rotation for haloperidol [ID50 = 0.067 mg (0.18 m̈mol)/kg], eticlopride [ID50 = 0.41 mg (1.2 m̈mol)/kg], clozapine [ID50 = 13 mg (40 m̈mol)/kg], and SCH 23390 [ID50 > 90 mg (313 m̈mol)/kg] closely parallels their rank order affinity for binding to either the D2 or the D3 receptor. Pretreatment with the non-DA receptor antagonists ritanserin (serotonin 5HT2), scopolamine (muscarinic cholinergic), propranolol (betaadrenergic), or naltrexone (opiate), each at relevant pharmacological doses, failed to reduce 7-OH-DPAT rotation. Taken together, these results are consistent with mediation of 7-OH-DPAT-induced rotational behavior via an agonist interaction with one or more DA receptors. ©1995 Wiley-Liss, Inc.
    Drug Development Research 10/2004; 34(4):329 - 335. · 0.87 Impact Factor
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    ABSTRACT: Corticotropin-releasing factor(1) (CRF(1)) antagonists may be effective in the treatment of anxiety disorders with fewer side effects compared with classic benzodiazepines. The behavioral effects of DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] and its effects on the hypothalamic-pituitary-adrenal (HPA) axis were related to its levels in plasma and estimated occupancy of central CRF(1) receptors. DMP904 (10-30 mg/kg, p.o.) and alprazolam (10 mg/kg, p.o.) increased time spent in open arms of an elevated-plus maze. In addition, acutely or chronically (14 days) administered DMP904 (1.0-30 mg/kg, p.o.) and acute alprazolam (1.0-3.0 mg/kg, p.o.) significantly reduced exit latency in the defensive withdrawal model of anxiety in rats, suggesting that tolerance may not develop to the anxiolytic-like effects of DMP904 in this model of anxiety. Acutely, DMP904 reversed the stress-induced increase in plasma corticosterone levels in defensive withdrawal at doses of 3.0 mg/kg and higher. These doses also resulted in levels of DMP904 in plasma similar to (for anxiolytic-like effects) or 4-fold higher (for effects on the HPA axis) than the in vitro IC(50) value for binding affinity at CRF(1) receptors and greater than 50% occupancy of CRF(1) receptors. Unlike alprazolam, DMP904 did not produce sedation, ataxia, or chlordiazepoxide-like subjective effects (as measured by locomotor activity, rotorod performance, and chlordiazepoxide discrimination assays, respectively) at doses at least 3-fold higher than anxiolytic-like doses. In conclusion, anxiolytic-like effects and effects on the stress-activated HPA axis of DMP904 in the defensive withdrawal model of anxiety required 50% or greater occupancy of central CRF(1) receptors. This level of CRF(1) receptor occupancy resulted in fewer motoric side effects compared with classic benzodiazepines.
    Journal of Pharmacology and Experimental Therapeutics 05/2004; 309(1):293-302. · 3.89 Impact Factor
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    ABSTRACT: Compounds with a mechanism of action different from benzodiazepines may retain the anxiolytic effects of benzodiazepines with fewer side effects. CRF(1) antagonists have anxiolytic-like effects but may have different discriminative stimulus (DS) effects compared with benzodiazepines. The present study evaluated the similarity of DS effects of a CRF(1) antagonist DMP696 to the benzodiazepine chlordiazepoxide and the ability of DMP696 to produce DS effects on its own using drug discrimination procedures, as well as its anxiolytic-like effects after acute or chronic administration. Rats were trained to discriminate chlordiazepoxide (5.0 mg/kg, IP, 30 min prior to session) from vehicle under a fixed-ratio 10 schedule of food reinforcement and drug- or vehicle-lever selection following administration of DMP696 was determined. The effects of DMP696 on latency to exit a dark chamber (defensive withdrawal model of anxiety) were used as an index of anxiolytic-like activity. In chlordiazepoxide-trained rats, DMP696 (1.0-100 mg/kg, PO) resulted in most of the animals selecting the vehicle lever, as did another anxiolytic, the 5-HT(1A) partial agonist buspirone (0.3-10 mg/kg, IP). DMP696 reduced exit latency in defensive withdrawal at 10 mg/kg administered either acutely or chronically for 14 days. Thus, the doses of DMP696 studied in drug discrimination were up to 10-fold higher than those active in the anxiety model. In addition, DMP696 (10-60 mg/kg, PO) could not be established as a DS under the conditions used in this study. In a subsequent study, chlordiazepoxide was established as a DS in these same animals. Lack of substitution of DMP696 for the chlordiazepoxide DS in rats and its inability to acquire DS properties suggest that the DS effects of DMP696 differ from those of benzodiazepines.
    Psychopharmacology 05/2003; 166(4):408-15. · 4.06 Impact Factor
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    ABSTRACT: 4-(1,3-Dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine (DMP696) is a highly selective and potent, nonpeptide corticotropin-releasing factor 1 (CRF(1)) antagonist. In this study, we measured in vivo CRF(1) receptor occupancy of DMP696 by using ex vivo ligand binding and quantitative autoradiography and explored the relationship of receptor occupancy with plasma and brain exposure and behavioral efficacy. In vitro affinity (IC(50)) of DMP696 to brain CRF(1) receptors measured using the brain section binding autoradiography in this study is similar to that assessed using homogenized cell membrane assays previously. The ex vivo binding assay was validated by demonstrating that potential underestimation of receptor occupancy with this procedure could be minimized by identifying an appropriate in vitro incubation time (40 min) based upon the dissociation kinetics of DMP696. Orally administrated DMP696 dose dependently occupied CRF(1) receptors in the brain, with ~60% occupancy at 3 mg/kg. In the defensive withdrawal test of anxiety, this dose of DMP696 produced approximately 50% reduction in the exit latency. The time course of plasma and brain drug levels paralleled that of receptor occupancy, with peak exposure at 90 min after dosing. The plasma-free concentration of DMP696 corresponding to 50% CRF(1) receptor occupancy (in vivo IC(50), 1.22 nM) was similar to the in vitro IC(50) (~1.0 nM). Brain concentrations of DMP696 were over 150-fold higher than the plasma-free levels. In conclusion, doses of DMP696 occupying over 50% brain CRF(1) receptors are consistent with doses producing anxiolytic efficacy in the defense withdrawal test of anxiety, and the IC(50) value estimated in vivo based on plasma-free drug concentrations is consistent with the in vitro IC(50) value.
    Journal of Pharmacology and Experimental Therapeutics 05/2003; 305(1):86-96. · 3.89 Impact Factor
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    ABSTRACT: The discovery of N-substituted-pyridoindolines and their binding affinities at the 5-HT(2A), 5-HT(2C) and D(2) receptors, and in vivo efficacy as 5-HT(2A) antagonists is described. The structure-activity relationship of a series of core tetracyclic derivatives with varying butyrophenone sidechains is also discussed. This study has led to the identification of potent, orally bioavailable 5-HT(2A)/D(2) receptor dual antagonists as potential atypical antipsychotics.
    Bioorganic & Medicinal Chemistry Letters 03/2003; 13(4):767-70. · 2.34 Impact Factor
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    ABSTRACT: A series of high affinity CRF receptor ligands with an imidazo[4,5-b]pyridine core is described. Individual analogues were synthesized and tested in a rat CRF receptor binding assay. The best compounds were further tested in the dog N-in-1 pharmacokinetic model to assess plasma levels at 1mg/kg (po) and in the rat situational anxiety model to assess anxiolytic efficacy at 3mg/kg (po). The structure-activity relationships for good receptor binding affinity are described herein.
    Bioorganic & Medicinal Chemistry Letters 02/2003; 13(1):125-8. · 2.34 Impact Factor
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    ABSTRACT: CRF(1) antagonists may be effective in the treatment of anxiety disorders while having fewer side effects compared with classical benzodiazepines. The effects of a small molecule selective CRF(1) antagonist DMP696 on anxiety-like behaviors and stress-induced increases in corticosterone in rats exposed to a novel environment and on locomotor activity and motor coordination were determined in rats. These effects of DMP696 were compared with those produced by the classical benzodiazepine chlordiazepoxide (CDP). DMP696 or CDP were administered PO, 60 minutes before behavioral testing in rats. Their effects on latency to exit a dark chamber and stress-induced increase in corticosterone in the Defensive Withdrawal test (an animal model of anxiety), locomotor activity, and rotorod performance (measure of ataxia) were determined. DMP696 significantly reduced exit latency and reversed the stress-induced increase in corticosterone in the Defensive Withdrawal test at doses of 3.0-10 mg/kg and higher. In contrast, CDP significantly decreased exit latency at 10 and 30 mg/kg, but not at 100 mg/kg, due to concurrent non-specific side effects. Unlike DMP696, CDP had no effect on the stress-induced increase in corticosterone at lower doses, but resulted in a significant increase at higher doses. DMP696 did not reduce locomotor activity or impair motor coordination at doses up to 30-fold higher than doses effective in the Defensive Withdrawal model. In contrast, CDP produced significant sedation and ataxia at the same doses that were effective in reducing exit latency. These data suggest that the CRF(1) antagonist DMP696 might retain the therapeutic benefits of classical benzodiazepines but have fewer motoric side effects.
    Psychopharmacology 01/2003; 165(1):86-92. · 4.06 Impact Factor