ABSTRACT
The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.
Subject(s)
Drug Discovery , Piperidines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Sleep Wake Disorders/drug therapy , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Orexin Receptors , Piperidines/chemical synthesis , Piperidines/chemistry , Rats , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.
Subject(s)
Receptors, Gastrointestinal Hormone/agonists , Receptors, Neuropeptide/agonists , Sulfonamides/pharmacology , Sulfones/pharmacology , Animals , Binding Sites , CHO Cells , Chemistry, Pharmaceutical , Cricetinae , Cricetulus , Drug Design , Drug Discovery , Models, Chemical , Molecular Structure , Structure-Activity RelationshipABSTRACT
High-throughput screening resulted in the identification of a series of novel motilin receptor agonists with relatively low molecular weights. The series originated from an array of biphenyl derivatives designed to target 7-transmembrane (7-TM) receptors. Further investigation of the structure-activity relationship within the series resulted in the identification of compound (22) as a potent and selective agonist at the motilin receptor.
Subject(s)
Receptors, Gastrointestinal Hormone/agonists , Receptors, Gastrointestinal Hormone/chemistry , Receptors, Neuropeptide/agonists , Receptors, Neuropeptide/chemistry , Animals , Binding Sites , Cell Membrane/metabolism , Chemistry, Pharmaceutical/methods , Combinatorial Chemistry Techniques , Drug Design , Drug Evaluation, Preclinical , Humans , Models, Chemical , Molecular Structure , Receptors, G-Protein-Coupled/metabolism , Recombinant Proteins/chemistry , Structure-Activity RelationshipABSTRACT
6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.
Subject(s)
Benzothiazoles/chemical synthesis , Chemistry, Pharmaceutical/methods , Niacinamide/analogs & derivatives , Niacinamide/chemical synthesis , TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/chemistry , Administration, Oral , Animals , Benzothiazoles/pharmacology , Capsaicin/chemistry , Cell Line , Drug Design , Guinea Pigs , Humans , Inflammation , Inhibitory Concentration 50 , Models, Chemical , Niacinamide/chemistry , Niacinamide/pharmacology , RatsABSTRACT
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
Subject(s)
Antidepressive Agents, Tricyclic/chemical synthesis , Brain/drug effects , Chemistry, Pharmaceutical/methods , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemical synthesis , Animals , Antidepressive Agents, Tricyclic/pharmacology , Blood-Brain Barrier/drug effects , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/chemistry , Humans , Hydrogen Bonding , Microsomes/drug effects , Models, Chemical , Molecular Conformation , Protein Isoforms , Rats , Serotonin Antagonists/pharmacologyABSTRACT
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.
Subject(s)
Alzheimer Disease/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Combinatorial Chemistry Techniques , Ethylamines/chemical synthesis , Ethylamines/pharmacology , Alzheimer Disease/drug therapy , Amyloid beta-Protein Precursor/antagonists & inhibitors , Crystallography, X-Ray , Ethylamines/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.
Subject(s)
Alzheimer Disease/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Combinatorial Chemistry Techniques , Ethylamines/chemical synthesis , Ethylamines/pharmacology , Alzheimer Disease/drug therapy , Amyloid beta-Protein Precursor/antagonists & inhibitors , Animals , Asparagine/chemistry , Crystallography, X-Ray , Disease Models, Animal , Ethylamines/chemistry , Fluorine/chemistry , Mice , Molecular Structure , Nanotechnology , Structure-Activity RelationshipABSTRACT
Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.
Subject(s)
Carbon/chemistry , Pyridines/chemistry , Receptors, Gastrointestinal Hormone/agonists , Receptors, Neuropeptide/agonists , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Gastrins/chemistry , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Pyridines/chemical synthesis , Pyridines/pharmacology , Rabbits , Rats , Receptors, Gastrointestinal Hormone/chemistry , Receptors, Neuropeptide/chemistryABSTRACT
This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures.
Subject(s)
Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Combinatorial Chemistry Techniques , Ethylamines/chemical synthesis , Ethylamines/pharmacology , Alzheimer Disease/drug therapy , Amyloid beta-Protein Precursor/antagonists & inhibitors , Crystallography, X-Ray , Ethylamines/chemistry , Humans , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
On June 15, 2006, the Society for Medicines Research held a one-day meeting in Harlow, United Kingdom, entitled Translational Sciences-Turning Drug-like Molecules into Medicines. The meeting brought together speakers from Europe representing the pharmaceutical industry and provided an overview on some of the latest approaches in a range of areas such as predictive toxicology, translational biology, in vitro-in vivo extrapolation, pharmacokinetic/pharmacodynamic modeling, and the use of biomarkers and surrogate endpoints.
Subject(s)
Drug Design , Drug Therapy , Pharmacokinetics , Toxicology , Animals , Humans , Models, AnimalABSTRACT
dopamine D3 receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D3 receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D3 receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D3 receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.
Subject(s)
Brain/drug effects , Cocaine-Related Disorders/drug therapy , Dopamine Antagonists/therapeutic use , Dopamine D2 Receptor Antagonists , Reward , Tetrahydroisoquinolines , Animals , Behavior, Animal/drug effects , Brain/physiopathology , Catalepsy/chemically induced , Catalepsy/physiopathology , Cocaine/administration & dosage , Cocaine-Related Disorders/physiopathology , Conditioning, Operant/drug effects , Dopamine Antagonists/adverse effects , Dose-Response Relationship, Drug , Electric Stimulation , Electrodes, Implanted , Haloperidol/adverse effects , Haloperidol/therapeutic use , Male , Nitriles/adverse effects , Nitriles/therapeutic use , Quinolines/adverse effects , Quinolines/therapeutic use , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3 , Reinforcement, Psychology , Secondary Prevention , Self Administration , Spatial Behavior/drug effectsABSTRACT
At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.
Subject(s)
Antipsychotic Agents/chemical synthesis , Benzazepines/chemical synthesis , Dopamine Antagonists/chemical synthesis , Dopamine D2 Receptor Antagonists , Sulfones/chemical synthesis , Action Potentials/drug effects , Administration, Oral , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Biological Availability , CHO Cells , Catalepsy/chemically induced , Cocaine/pharmacology , Conditioning, Classical/drug effects , Cricetinae , Dopamine/metabolism , Dopamine Antagonists/pharmacokinetics , Dopamine Antagonists/pharmacology , Drug Design , Humans , Male , Neurons/drug effects , Neurons/metabolism , Neurons/physiology , Prolactin/blood , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D3 , Structure-Activity Relationship , Substantia Nigra/cytology , Substantia Nigra/drug effects , Substantia Nigra/physiology , Sulfones/pharmacokinetics , Sulfones/pharmacology , Ventral Tegmental Area/cytology , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/physiologyABSTRACT
N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human motilin receptor and also at the native rabbit motilin receptor where its agonist activity results in potentiation of the amplitude of neuronal-mediated contractions of isolated gastric antrum tissue. Compound 12 also possesses highly promising pharmacokinetic profiles in both rat and dog, and these results, in combination with further profiling in human native tissue and an in vivo model of gastrointestinal transit in the rabbit, have led to its selection as a candidate for further development.
Subject(s)
Drug Discovery , Gastrointestinal Agents/pharmacology , Piperazines/pharmacology , Piperidines/pharmacology , Pyloric Antrum/drug effects , Receptors, Gastrointestinal Hormone/agonists , Receptors, Neuropeptide/agonists , Animals , Dogs , Gastrointestinal Motility/drug effects , Humans , Muscle Contraction/drug effects , Piperazines/chemistry , Piperidines/chemistry , Pyloric Antrum/physiology , Rabbits , RatsABSTRACT
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Subject(s)
Receptors, Serotonin/metabolism , Serotonin Agents/metabolism , Administration, Oral , Biological Availability , Ligands , Serotonin Agents/pharmacokineticsABSTRACT
A concise and convergent eight-step synthesis of the antifungal metabolite monocerin 1 is reported. The key step involves an allylsilane metathesis/aldehyde condensation sequence to establish the core 2,3,5-trisubstituted tetrahydrofuran. End-game approaches based around intramolecular Heck chemistry revealed an interesting example of formal 6-endo cyclisation, the origin of which was probed using model substrates. The synthesis was ultimately completed by a strategy involving stepwise oxidative cleavage of the C3-ethenyl substituent.
Subject(s)
Lactones/chemical synthesis , Lactones/chemistry , Molecular Structure , StereoisomerismABSTRACT
We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
Subject(s)
Amides/chemistry , Amides/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacokinetics , Brain/drug effects , Brain/metabolism , Cattle , Computational Biology , Humans , Ligands , Models, Molecular , Molecular Structure , Receptors, Somatostatin/chemistry , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Sulfur/chemistryABSTRACT
A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.
Subject(s)
Amides/pharmacology , Biphenyl Compounds/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Anilides/chemistry , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/chemistry , Humans , Molecular Structure , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
Starting from the high throughput screening hit (3), novel N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl carboxamides have been identified as potent antagonists of the ion channel TRPV1. The N-quinolinylnicotinamide (46) showed excellent potency at human, guinea pig and rat TRPV1, a favourable in vitro DMPK profile and activity in an in vivo model of inflammatory pain.
Subject(s)
Benzamides/chemistry , Benzamides/pharmacology , Isoquinolines/chemistry , Isoquinolines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Animals , Benzamides/chemical synthesis , Capsaicin/pharmacology , Guinea Pigs , Humans , Isoquinolines/chemical synthesis , Liver/drug effects , Liver/metabolism , Molecular Structure , Quinolines/chemical synthesis , Rats , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
Small molecule antagonists of the vanilloid receptor TRPV1 (also known as VR1) are disclosed. Pyrrolidinyl ureas such as 8 and 15 (SB-705498) emerged as lead compounds following optimisation of the previously described urea SB-452533. Pharmacological studies using electrophysiological and FLIPR-Ca2+-based assays showed that compounds such as 8 and 15 were potent antagonists versus the multiple chemical and physical modes of TRPV1 activation (namely capsaicin, acid and noxious heat). Furthermore, 15 possessed suitable developability properties to enable progression of this compound into in vivo studies and subsequently clinical development.