ABSTRACT
The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Drug Design , Drug Discovery , Dysmenorrhea/drug therapy , Hormone Antagonists/chemical synthesis , Hormone Antagonists/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Benzodiazepines/chemistry , Benzodiazepines/metabolism , Drug Stability , Female , Hormone Antagonists/chemistry , Hormone Antagonists/metabolism , Humans , Microsomes/physiology , Molecular Structure , Triazoles/chemistry , Triazoles/metabolismABSTRACT
New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.
Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Norepinephrine , Piperazines/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Urinary Incontinence, Stress/drug therapy , Adrenergic Uptake Inhibitors/metabolism , Adrenergic Uptake Inhibitors/pharmacokinetics , Animals , Dogs , Humans , Piperazines/metabolism , Piperazines/pharmacology , Selective Serotonin Reuptake Inhibitors/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adrenergic Uptake Inhibitors/chemistry , Anilides/chemistry , Benzamides/chemistry , Central Nervous System/metabolism , Pyrrolidines/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacokinetics , Anilides/chemical synthesis , Anilides/pharmacology , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Cell Line , Dogs , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacokinetics , Humans , Norepinephrine/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Rats , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Derivatives of N-[(3S)-pyrrolidin-3-yl]benzamides are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Structure-activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenyl ring; consequently, selective NRIs and dual NSRIs were prepared. Benzamide 11e was identified as a potent NRI with good selectivity over SRI and DRI, good in vitro metabolic stability, weak CYP inhibition and low affinity for ion channels. Evaluation in vivo, in rat microdialysis experiments, showed 11e increased noradrenaline levels by up to 350% confirming good CNS penetration. Benzamide 11e was differentiated from previous NRIs as it was significantly less lipophilic (DeltaclogP -0.9).
Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Benzamides/chemical synthesis , Central Nervous System Agents/chemical synthesis , Central Nervous System/metabolism , Norepinephrine/metabolism , Pyrrolidines/chemical synthesis , Adrenergic Uptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/pharmacology , Animals , Benzamides/chemistry , Benzamides/pharmacology , Cell Line , Central Nervous System Agents/chemistry , Central Nervous System Agents/pharmacology , Drug Design , Humans , Microsomes, Liver/metabolism , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , RatsABSTRACT
2-((R-5-chloro-4-methoxymethyl-indan-1-yl)-1H-imidazole (PF-3774076) is a central nervous system (CNS) penetrant, potent, selective, partial agonist at the human alpha1(A)-adrenoceptor, demonstrating efficacy and selectivity in a range of binding and functional assays. In vivo, PF-3774076 increases peak urethral pressure in anesthetized female dogs in a dose-dependent manner, inducing changes in both the proximal and distal portions of the urethra via a central mechanism of action. The profile of this compound suggests that a CNS penetrant partial agonist at the alpha1(A)-adrenoceptor may offer significant benefit in stress urinary incontinence (SUI). However, despite partial agonism at the alpha1(A)-adrenoceptor and selectivity over alpha1(B)- and alpha1(D)-adrenoceptors, PF-3774076 did not offer the necessary degree of separation over cardiovascular events when assessed in in vivo models of cardiovascular function. This may be due to activation of both peripheral and central alpha1(A)-adrenoceptors. These data indicate that although central, partial alpha1(A)-agonists may offer significant benefit in the treatment of SUI, it may not be possible to achieve the desired level of urethral selectivity over cardiovascular events with this class of agent.
Subject(s)
Adrenergic alpha-1 Receptor Agonists , Adrenergic alpha-Agonists/pharmacology , Imidazoles/pharmacology , Urethra/drug effects , Animals , Blood Pressure/drug effects , CHO Cells , Cell Line , Cricetinae , Cricetulus , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Dogs , Female , Heart Rate/drug effects , Hemodynamics/drug effects , Humans , Radioligand Assay , Receptors, Adrenergic, alpha-1/biosynthesis , Sulfonamides/pharmacology , Telemetry , Urethra/metabolismABSTRACT
Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.
Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Norepinephrine/metabolism , Piperidines/chemistry , Pyrrolidines/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacokinetics , Animals , Drug Design , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Rats , Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Novel imidazole frameworks have been identified as potent partial agonists of the alpha(1A) adrenergic receptor, with good selectivity over the alpha(1B), alpha(1D) and alpha(2A) receptor sub-types. Nitrile 28 possessed attractive CNS drug-like properties with good membrane permeability and no P-pg mediated efflux. 28 also possessed excellent solubility, metabolic stability and wide ligand selectivity.
Subject(s)
Adrenergic alpha-1 Receptor Agonists , Imidazoles/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adrenergic alpha-2 Receptor Agonists , Animals , Cell Line , Dogs , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Adrenergic, alpha-2/metabolismABSTRACT
A novel series of central nervous system (CNS) penetrant indane 2-imidazoles have been identified as potent, partial agonists of the alpha(1A) adrenergic receptor, having good selectivity over the alpha(1B), alpha(1D) and alpha(2) sub-types. A key structural motif to impart selectivity is a methylene spacer between the indane and a pendant substituent, which includes heterocycles, sulphones and ethers. Introduction of an ortho-halogen to this group led to a lowering of intrinsic efficacy (E(max)).
Subject(s)
Adrenergic alpha-1 Receptor Agonists , Central Nervous System/drug effects , Chemistry, Pharmaceutical/methods , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Amino Acid Motifs , Chromatography, High Pressure Liquid , Drug Design , Halogens/chemistry , Humans , Kinetics , Microsomes, Liver/drug effects , Models, Chemical , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.
Subject(s)
Benzylamines/chemical synthesis , Benzylamines/pharmacology , Phenyl Ethers/chemical synthesis , Phenyl Ethers/pharmacology , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Benzylamines/chemistry , Combinatorial Chemistry Techniques , Humans , Molecular Structure , Phenyl Ethers/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Carboxamide 9e, carbamate 11b and sulfonamide 13a were identified as potent NRIs with excellent selectivity over SRI and DRI, good in vitro metabolic stability and weak CYP inhibition. Carbamate 11b demonstrated superior transit performance in MDCK-mdr1 cell lines with minimal P-gp efflux which was attributed to reduced HBA capacity of the carbamate group. Evaluation in vivo, in rat microdialysis experiments, showed 11b increased noradrenaline levels by 400% confirming good CNS penetration.
Subject(s)
Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Animals , Central Nervous System/drug effects , Combinatorial Chemistry Techniques , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Pyrrolidines/chemistry , Rats , Selective Serotonin Reuptake Inhibitors/chemistry , StereoisomerismABSTRACT
The structure-activity relationship and the synthesis of novel N-benzyl-N-(pyrrolidin-3-yl)carboxamides as dual serotonin (5-HT) and noradrenaline (NA) monoamine reuptake inhibitors are described. Compounds such as 18 exhibited dual 5-HT and NA reuptake inhibition, good selectivity over dopamine (DA) reuptake inhibition and drug-like physicochemical properties consistent with CNS target space. Compound 18 was selected for further preclinical evaluation.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Norepinephrine/analysis , Pyrrolidines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin/analysis , Amides/chemistry , Animals , Central Nervous System/drug effects , Combinatorial Chemistry Techniques , Cytochrome P-450 CYP2D6 Inhibitors , Dogs , Dopamine Uptake Inhibitors/pharmacology , Drug Design , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Inhibitory Concentration 50 , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Conformation , Pyrrolidines/pharmacology , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A series of substituted benzylamines 2-48 were prepared as part of a strategy to identify structurally differentiated and synthetically more accessible selective serotonin reuptake inhibitors, relative to clinical candidate 1. In particular, 44 and 48; demonstrated low nanomolar potency and good selectivity, in a structurally simplified template and, in vivo, very low Vdu, significantly lower than l, and a more rapid T(max), consistent with our clinical objectives.
Subject(s)
Benzylamines/chemistry , Chemistry, Pharmaceutical/methods , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Molecular Conformation , Receptors, Serotonin/metabolism , Serotonin/chemistry , Serotonin/metabolism , Structure-Activity RelationshipABSTRACT
Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.
Subject(s)
Drug Design , Morpholines/chemical synthesis , Morpholines/pharmacology , Norepinephrine/metabolism , Serotonin/metabolism , Cells, Cultured , Humans , Liver/drug effects , Liver/metabolism , Molecular Structure , Morpholines/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Novel 2-imidazoles have been identified as potent partial agonists of the alpha(1A) adrenergic receptor, with good selectivity over the alpha(1B), alpha(1D) and alpha(2A) receptor sub-types. Sulfonamide 23 possessed attractive drug-like properties with respect to physicochemical and ADME properties and wide ligand selectivity.
Subject(s)
Adrenergic alpha-1 Receptor Agonists , Adrenergic alpha-Agonists/therapeutic use , Imidazoles/therapeutic use , Urinary Incontinence/drug therapy , Adrenergic alpha-2 Receptor Agonists , Adrenergic alpha-Agonists/chemical synthesis , Humans , Imidazoles/chemical synthesis , Models, Chemical , Receptors, Adrenergic, alpha-1 , Receptors, Adrenergic, alpha-2 , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted that potent dual SNRI activity was only achievable at c log P>3.5. The series was found to possess significant polypharmacology issues, and we concluded that this off-target promiscuity was related to lipophilicity.
Subject(s)
Amines/pharmacology , Hepatocytes/drug effects , Norepinephrine/antagonists & inhibitors , Phenyl Ethers/pharmacology , Pyridines/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin 5-HT1 Receptor Antagonists , Amines/chemical synthesis , Hepatocytes/metabolism , Humans , Inhibitory Concentration 50 , Models, Chemical , Phenyl Ethers/chemical synthesis , Pyridines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
[4-(Phenoxy)pyridine-3-yl]methylamines are disclosed as a new series of selective noradrenaline reuptake inhibitors (NRI). Structure-activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenoxy ring. Compound 31 demonstrated potent NRI activity combined with good selectivity over serotonin and dopamine reuptake and no significant off-target pharmacology.
Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Methylamines/pharmacology , Norepinephrine/antagonists & inhibitors , Pyridines/pharmacology , Adrenergic Uptake Inhibitors/chemical synthesis , Animals , Biological Transport , Caco-2 Cells , Cytochrome P-450 Enzyme Inhibitors , Dopamine/metabolism , Dopamine Uptake Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/metabolism , Extracellular Fluid/drug effects , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Methylamines/chemical synthesis , Microdialysis , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Prefrontal Cortex/drug effects , Pyridines/chemical synthesis , Rats , Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A series of N-benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine monoamine reuptake inhibitors are described. Selective dual 5-HT and NA reuptake inhibition was achieved, and analogues with weak CYP2D6 inhibition, good human in vitro metabolic stability and wide ligand selectivity, such as 12b, were identified.
Subject(s)
Chemistry, Pharmaceutical/methods , Cytochrome P-450 CYP2D6 Inhibitors , Norepinephrine/antagonists & inhibitors , Pyrrolidines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Amines/chemistry , Drug Design , Ether-A-Go-Go Potassium Channels/chemistry , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Inhibitory Concentration 50 , Ligands , Microsomes/drug effects , Microsomes/metabolism , Models, Chemical , Molecular Conformation , Pyrrolidines/pharmacology , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacologyABSTRACT
A series of substituted glutaramides were synthesised using Candoxatrilat 1 as a lead and evaluated for potency against neutral endopeptidase (NEP) as a potential treatment for female sexual arousal disorder (FSAD). In this paper, we describe studies in which we were able to increase NEP activity substantially over the levels reported for previous compounds from this programme by appropriate substitution in both the P(1)(') and P(2)(') regions. Optimisation led to the 4-chlorophenpropylamide S-30 which was selected as a candidate for further study.
Subject(s)
Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/chemical synthesis , Neprilysin/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/chemical synthesis , Sexual Dysfunctions, Psychological/drug therapy , Animals , Cyclohexanecarboxylic Acids/pharmacokinetics , Dogs , Female , Humans , Hydrogen-Ion Concentration , Male , Molecular Structure , Protease Inhibitors/pharmacokinetics , Rabbits , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Substrate Specificity , SwineABSTRACT
Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)
Subject(s)
Acids, Carbocyclic/chemical synthesis , Amides/chemical synthesis , Neprilysin/antagonists & inhibitors , Pentanoic Acids/chemical synthesis , Sexual Dysfunctions, Psychological/drug therapy , Thiadiazoles/chemical synthesis , Acids, Carbocyclic/pharmacokinetics , Acids, Carbocyclic/pharmacology , Amides/pharmacokinetics , Amides/pharmacology , Animals , CHO Cells , Clitoris/blood supply , Clitoris/drug effects , Cricetinae , Cricetulus , Dogs , Female , Humans , Male , Pentanoic Acids/pharmacokinetics , Pentanoic Acids/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rabbits , Rats , Recombinant Proteins/antagonists & inhibitors , Regional Blood Flow/drug effects , Species Specificity , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/pharmacokinetics , Thiadiazoles/pharmacology , Vagina/blood supply , Vagina/drug effectsABSTRACT
The synthesis and structure-activity relationships of a novel series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake is described. Two compounds possessed comparable in vitro profiles to the dual reuptake inhibitor duloxetine.
