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3.
Curr Opin Pharmacol ; 35: vi, 2017 08.
Article in English | MEDLINE | ID: mdl-29241831
5.
Curr Opin Pharmacol ; 35: 89-93, 2017 08.
Article in English | MEDLINE | ID: mdl-28864032

ABSTRACT

This article is in memory of Professor Norman Bowery (1944-2016). Norman was a pharmacologist who spent most of his career researching the pharmacology of γ-aminobutyric acid (GABA). He discovered a novel metabotropic receptor subtype, GABAB, that is pharmacologically, and structurally different from the original ionotropic receptor now designated as GABAA. In his research he also studied the neurotransmitters glutamate and substance P, two molecules whose release in parts of the spinal cord is inhibited by baclofen a GABAB receptor agonist. Norman was interested in the therapeutic potential of interacting with the GABAB receptor, in particular spasticity, pain and absence epilepsy.


Subject(s)
Pharmacology/history , Receptors, GABA-B/history , History, 20th Century , History, 21st Century , gamma-Aminobutyric Acid
6.
Curr Opin Pharmacol ; 14: 50-3, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24565012

ABSTRACT

Clinical Pharmacology in Neuroscience Drug Discovery in recent years has concentrated on First Time in Human safety and pharmacokinetics. The more traditional pharmacological research in humans has been reduced mainly as a response to the difficulty of developing human pharmacology models in neuroscience diseases. As a consequence, opportunities are being missed to aid in target selection and in target validation. The decision of big Pharma to reduce investment from the Neurosciences has had implications for clinical pharmacologists in this area. It remains to be seen whether academia, government laboratories and contract houses will respond to the challenge of carrying out increased Clinical Pharmacology in the Neurosciences.


Subject(s)
Drug Design , Models, Biological , Pharmacology, Clinical , Animals , Drug Discovery/methods , Drug Industry/methods , Humans , Neurosciences/methods , Research Design
7.
Sleep ; 36(12): 1823-30, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24293756

ABSTRACT

STUDY OBJECTIVES: Investigate the hypnotic effects of repeated doses of neurokinin-1 receptor antagonist, vestipitant, in primary insomnia. DESIGN: Randomized, double-blind, placebo-controlled 28-day parallel-group study. SETTING: Eleven sleep centers in Germany. PATIENTS: One hundred sixty-one patients with primary insomnia. INTERVENTIONS: Patients received vestipitant (15 mg) or placebo for 28 days; 2-night polysomnographic assessment occurred on nights 1/2 and 27/28. MEASUREMENTS AND RESULTS: Wake after sleep onset (WASO) was improved on nights 1/2 and 27/28 (ratio, vestipitant versus placebo [95% confidence interval]: 0.76 [0.65, 0.90], P = 0.001 and 0.79 [0.65, 0.96], P = 0.02, respectively), demonstrating maintenance of the effect following repeated dosing. Latency to persistent sleep was shorter with vestipitant on nights 1/2 (P = 0.0006 versus placebo), but not on nights 27/28. Total sleep time (TST) improved with vestipitant (nights 1/2: P < 0.0001, nights 27/28: P = 0.02 versus placebo). Next-day cognitive function tests demonstrated no residual effects of vestipitant (P > 0.05 versus placebo). Adverse events (AEs) occurred in 25% of vestipitant patients versus 22% for placebo. Headache was the most common AE (8% of vestipitant patients versus 9% for placebo). CONCLUSIONS: Vestipitant improved sleep maintenance in patients with primary insomnia, with no associated next-day cognitive impairment. The effects on wake after sleep onset and total sleep time were maintained following repeated dosing.


Subject(s)
Fluorobenzenes/therapeutic use , Neurokinin-1 Receptor Antagonists/therapeutic use , Piperidines/therapeutic use , Sleep Initiation and Maintenance Disorders/drug therapy , Adult , Double-Blind Method , Female , Humans , Male , Middle Aged , Polysomnography , Treatment Outcome , Young Adult
8.
J Recept Signal Transduct Res ; 33(6): 333-7, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24106886

ABSTRACT

The difference in location between the receptor occupancy curve of an agonist and its functional response has been described as receptor reserve. This "reserve" for a specific receptor has been found to differ from tissue to tissue and between agonists acting on the same tissue. Recently, two structurally different neurokinin 1 (NK1) receptor antagonists were taken into human and both were tested as antidepressants and for insomnia. Vestipitant and Casopitant both have high affinity for the human NK1 receptor (pKi = 9.4 and 10.2, respectively). In human, at the chosen clinical doses, receptor occupancy was measured in the frontal cortex, at 24 hours post administration, as ∼90% for vestipitant (15 mg) and ∼100% for casopitant (30 mg). In patients with moderate to severe major depression, vestipitant given at 15 mg for 8 weeks showed no statistical significant benefit as measured by change in baseline in HAM-D total score; whereas casopitant at 80 mg achieved statistically significant improvement versus placebo at week 8 (LOCF HAMD17 = -2.7, p = 0.023). A lower dose of 30 mg showed a clear but not significant separation from placebo. However, in acute studies in insomnia, both vestipitant and casopitant at 15 mg and 30 mg, respectively, significantly reduced latency to persistent sleep, wakenings after sleep onset and increased total sleep time by similar amounts. These clinical results suggest that for major depression the receptor occupancy of an NK1 antagonist needs to be very high (almost 100%), whereas, for insomnia a lower occupation is sufficient to give clinical effect.


Subject(s)
Fluorobenzenes/administration & dosage , Piperazines/administration & dosage , Piperidines/administration & dosage , Receptors, Neurokinin-1/metabolism , Sleep Initiation and Maintenance Disorders/drug therapy , Antidepressive Agents/administration & dosage , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/physiopathology , Humans , Neurokinin-1 Receptor Antagonists/administration & dosage , Neurokinin-1 Receptor Antagonists/metabolism , Sleep Initiation and Maintenance Disorders/physiopathology , Tissue Distribution
9.
Bioorg Med Chem ; 19(14): 4257-73, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21689940

ABSTRACT

This article deals with the synthesis and the activities of some 1,5-dialkyl-3-arylureido-1,5-benzodiazepin-2,4-diones which were prepared as potential CCK2 antagonists, with the intention to find a possible follow up of our lead compound GV150013, showing an improved pharmacokinetic profile. The phenyl ring at N-5 was replaced with more hydrophilic substituents, like alkyl groups bearing basic functions. In some cases, the resolution of the racemic key intermediates 3-amino-benzodiazepines was also accomplished. Among the compounds synthesized and characterised so far in this class, the 5-morpholinoethyl derivative 54, was selected as potential follow up of GV150013 and submitted for further evaluation.


Subject(s)
Benzodiazepinones/pharmacology , Receptor, Cholecystokinin B/antagonists & inhibitors , Animals , Benzodiazepinones/chemical synthesis , Benzodiazepinones/chemistry , Dogs , Guinea Pigs , Mice , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship , Tissue Distribution
11.
Curr Opin Pharmacol ; 11(5): 528-33, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21704559

ABSTRACT

Scientific method in drug discovery has centered on generating a hypothesis (target identification) and hypothesis testing (target validation). Traditionally, both processes were performed using animal data, with the basic pharmacologist being pivotal. Many therapeutic areas that rely on human data to validate targets as animal models are seen as poorly predictive. Failures of molecules in Phase III for poor efficacy raise questions about target identification and validation. The clinical pharmacologist, working with the basic pharmacologist can play a major role in aiding target identification and by developing trial designs using small patient populations, mitigating the need for full Phase III studies to test the hypothesis. Technologies such as genomics, non-invasive imaging and proteomics are in the forefront of improving target identification and in some cases in providing paradigms for target validation in man.


Subject(s)
Drug Discovery/methods , Pharmacology, Clinical/methods , Animals , Clinical Trials as Topic , Humans
12.
J Med Chem ; 54(4): 1071-9, 2011 Feb 24.
Article in English | MEDLINE | ID: mdl-21229983

ABSTRACT

A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK(1) receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK(1) receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.


Subject(s)
Brain/drug effects , Brain/metabolism , Depressive Disorder/drug therapy , Neurokinin-1 Receptor Antagonists , Piperazines/chemical synthesis , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Animals , Behavior, Animal/drug effects , CHO Cells , Cricetinae , Cricetulus , Depressive Disorder/metabolism , Drug Discovery , Gerbillinae , Half-Life , Humans , Magnetic Resonance Spectroscopy , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperidines/chemistry , Piperidines/pharmacokinetics , Regression Analysis , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Infrared , Stereoisomerism
13.
Eur Neuropsychopharmacol ; 21(3): 221-9, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21194898

ABSTRACT

The substance P-neurokinin-1 receptor (SP-NK(1)R) system has been extensively studied in experimental models of stress, fear, and reward. Elevated cerebrospinal fluid (CSF) SP levels were reported previously in combat-related PTSD. No medication specifically targeting this system has been tested in PTSD. This proof-of-concept randomized, double-blind, placebo-controlled trial evaluated the selective NK(1)R antagonist GR205171 in predominately civilian PTSD. Following a 2-week placebo lead-in, 39 outpatients with chronic PTSD and a Clinician-Administered PTSD Scale (CAPS) score ≥50 were randomized to a fixed dose of GR205171 (N=20) or placebo (N=19) for 8weeks. The primary endpoint was mean change from baseline to endpoint in the total CAPS score. Response rate (≥50% reduction in baseline CAPS) and safety/tolerability were secondary endpoints. CSF SP concentrations were measured in a subgroup of patients prior to randomization. There was significant improvement in the mean CAPS total score across all patients over time, but no significant difference was found between GR205171 and placebo. Likewise, there was no significant effect of drug on the proportion of responders [40% GR205171 versus 21% placebo (p=0.30)]. An exploratory analysis showed that GR205171 treatment was associated with significant improvement compared to placebo on the CAPS hyperarousal symptom cluster. GR205171 was well-tolerated, with no discontinuations due to adverse events. CSF SP concentrations were positively correlated with baseline CAPS severity. The selective NK(1)R antagonist GR205171 had fewer adverse effects but was not significantly superior to placebo in the short-term treatment of chronic PTSD. (ClinicalTrials.gov Identifier: NCT 00211861, NCT 00383786).


Subject(s)
Neurokinin-1 Receptor Antagonists , Piperidines/therapeutic use , Stress Disorders, Post-Traumatic/drug therapy , Tetrazoles/therapeutic use , Adult , Double-Blind Method , Female , Humans , Male , Middle Aged , Piperidines/adverse effects , Placebos , Psychiatric Status Rating Scales , Substance P/cerebrospinal fluid , Tetrazoles/adverse effects , Time Factors , Treatment Outcome , Young Adult
14.
J Med Chem ; 52(10): 3238-47, 2009 May 28.
Article in English | MEDLINE | ID: mdl-19388677

ABSTRACT

In an effort to discover novel druglike NK(1) receptor antagonists a new series of suitably substituted C-phenylpiperazine derivatives was identified by an appropriate chemical exploration of related N-phenylpiperazine analogues, with the specific aim to maximize their in vitro affinity and optimize in parallel their pharmacokinetic profile. Among the compounds synthesized, 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) was identified as one of the most in vitro potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. On the basis of its preclinical profile, this compound was selected as a drug candidate.


Subject(s)
Neurokinin-1 Receptor Antagonists , Piperazines/chemistry , Piperidines/pharmacology , Administration, Oral , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Discovery , Drug Evaluation, Preclinical , Fluorobenzenes , Gerbillinae , Pharmacokinetics , Piperazines/pharmacology , Piperidines/pharmacokinetics , Structure-Activity Relationship
15.
J Med Chem ; 51(23): 7370-9, 2008 Dec 11.
Article in English | MEDLINE | ID: mdl-18989952

ABSTRACT

To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.


Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Female , Forelimb/drug effects , Gerbillinae , Humans , Male , Models, Chemical , Molecular Structure , Motor Activity/drug effects , Psychological Tests , Pyridines/chemistry , Pyrroles/chemistry , Rats , Rats, Sprague-Dawley , Stereoisomerism , Ultrasonics , Vocalization, Animal/drug effects
16.
Bioorg Med Chem ; 11(2): 171-83, 2003 Jan 17.
Article in English | MEDLINE | ID: mdl-12470711

ABSTRACT

Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models.


Subject(s)
Analgesics, Non-Narcotic/chemical synthesis , Analgesics, Non-Narcotic/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , CHO Cells , Combinatorial Chemistry Techniques , Cricetinae , Electrophysiology/methods , Humans , Inhibitory Concentration 50 , Pain Measurement/drug effects , Protein Binding , Protein Structure, Tertiary , Rats , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/genetics , Recombinant Fusion Proteins/antagonists & inhibitors , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Spinal Cord/drug effects , Spinal Cord/physiology , Structure-Activity Relationship , Xenopus laevis
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