ABSTRACT
A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.
Subject(s)
Imidazolines/pharmacology , Purinergic Antagonists/pharmacology , Receptors, Purinergic P2X7/drug effects , Administration, Oral , Animals , Biological Availability , Half-Life , Haplorhini , Imidazolines/administration & dosage , Imidazolines/chemistry , Imidazolines/pharmacokinetics , Purinergic Antagonists/administration & dosage , Purinergic Antagonists/chemistry , Purinergic Antagonists/pharmacokinetics , RatsABSTRACT
A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.
Subject(s)
Amides/pharmacology , Purinergic P2 Receptor Antagonists/pharmacology , Pyrrolidonecarboxylic Acid/chemistry , Receptors, Purinergic P2X7/drug effects , Amides/chemistry , Drug Discovery , Models, Molecular , Purinergic P2 Receptor Antagonists/chemistry , Structure-Activity RelationshipABSTRACT
A series of analogues of the pyrazole lead 1 were synthesized in which the heterocyclic core was replaced with an imidazole. A number of potent antagonists were identified and structure-activity relationships (SAR) were investigated both with respect to activity at the P2X(7) receptor and in vitro metabolic stability. Compound 10 was identified as a potent P2X(7) antagonist with reduced in vitro metabolism and high solubility.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Imidazoles/chemistry , Purinergic P2 Receptor Antagonists , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Pyrazoles/chemistry , Rats , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X7 , Structure-Activity RelationshipABSTRACT
Structure-activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund's adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res.1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain2006, 10, 537].
Subject(s)
Acetamides/chemistry , Purinergic P2X Receptor Antagonists , Pyrazoles/chemistry , Acetamides/chemical synthesis , Acetamides/therapeutic use , Administration, Oral , Animals , Disease Models, Animal , Humans , Pain/drug therapy , Pyrazoles/chemical synthesis , Rats , Receptors, Purinergic P2X7/metabolism , Structure-Activity RelationshipABSTRACT
High-throughput screening identified compound 1 as a potent P2X(7) receptor antagonist suitable for lead optimisation. Structure-activity relationships (SAR) of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties.
Subject(s)
Acetamides/chemistry , Anti-Infective Agents/chemical synthesis , Purinergic P2 Receptor Antagonists , Pyrazoles/chemical synthesis , Acetamides/chemical synthesis , Acetamides/pharmacokinetics , Administration, Oral , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacokinetics , High-Throughput Screening Assays , Humans , Injections, Intravenous , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Rats , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X7 , Structure-Activity RelationshipABSTRACT
A series of 3-amino-6-aryl-pyridazines have been identified as CB(2) agonists with high efficacy and selectivity against the CB(1) receptor. Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analogue 35, a compound with high potency in an in vivo model of inflammatory pain.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Isoquinolines/chemical synthesis , Pyridazines/chemical synthesis , Receptor, Cannabinoid, CB2/agonists , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Isoquinolines/chemistry , Isoquinolines/pharmacokinetics , Pain/drug therapy , Pyridazines/chemistry , Pyridazines/pharmacokinetics , Rats , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
2-Amino-5-aryl-pyridines, exemplified by compound 1, had been identified as a synthetically tractable series of CB(2) agonists from a high-throughput screen of the GlaxoSmithKline compound collection. Described herein are the results of an investigation of the structure-activity relationships (SAR) which led to the identification a number of potent and selective agonists.
Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Drug Design , Molecular Structure , Pyridines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
Subject(s)
Amines/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemical synthesis , Ethers/chemical synthesis , Pyrimidines/chemical synthesis , Sulfones/chemical synthesis , Amines/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Chemistry, Pharmaceutical/methods , Cyclooxygenase 2/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Disease Models, Animal , Drug Design , Ethers/pharmacology , Humans , Inflammation , Inhibitory Concentration 50 , Mice , Molecular Structure , Neurodegenerative Diseases/drug therapy , Pyrimidines/pharmacology , Rats , Sulfones/pharmacologyABSTRACT
Many years of work have been invested in the identification of potent and selective COX-2 inhibitors for the treatment of chronic inflammatory pain. One issue faced by workers is the balance between the lipophilicity required for potent enzyme inhibition and the physical properties necessary for drug absorption and distribution in vivo. Frequently approaches to reduce lipophilicity through introduction of polar functionality is hampered by highly challenging chemistry to prepare key molecules. We have complemented traditional synthetic chemistry with a biotransformations approach which efficiently provided access to an array of key target molecules.
Subject(s)
Cyclooxygenase 2 Inhibitors/chemical synthesis , Biotransformation , Chemistry, Pharmaceutical/methods , Cyclooxygenase 2/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Design , Humans , Inflammation/drug therapy , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Structure-Activity RelationshipABSTRACT
The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.
