ABSTRACT
Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.
Subject(s)
Cyclohexanols/chemistry , Isoxazoles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Administration, Oral , Amides/chemistry , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Capsaicin/toxicity , Cyclohexanols/pharmacokinetics , Cyclohexanols/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Isoxazoles/pharmacokinetics , Isoxazoles/therapeutic use , Microsomes, Liver/metabolism , Rats , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
Optimization of a water soluble, moderately potent lead series of isoxazole-3-carboxamides was conducted, affording a compound with the requisite balance of potency, solubility and physicochemical properties for in vivo use. Compound 8e was demonstrated to be efficacious in a rat model of inflammatory pain, following oral administration.
Subject(s)
Isoxazoles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Administration, Oral , Amides/chemical synthesis , Amides/chemistry , Amides/therapeutic use , Animals , Disease Models, Animal , Humans , Isoxazoles/chemical synthesis , Isoxazoles/therapeutic use , Pain/drug therapy , Rats , TRPV Cation Channels/metabolismABSTRACT
Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.
Subject(s)
Heterocyclic Compounds/pharmacokinetics , Receptor, Cannabinoid, CB1/agonists , Administration, Oral , Animals , Biological Availability , Drug Discovery , Heterocyclic Compounds/administration & dosage , RatsABSTRACT
Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
Subject(s)
Amides/chemistry , Antihypertensive Agents/chemistry , Cyclohexanols/chemistry , Isoxazoles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Cyclohexanols/chemical synthesis , Cyclohexanols/pharmacokinetics , Hyperthermia, Induced , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement of the benzimidazol-2-one moiety was explored. Compound 51 was found to be a high affinity, potent NOP receptor agonist with reduced affinity for the hERG channel.
Subject(s)
Benzimidazoles/chemistry , Narcotic Antagonists/chemistry , Piperidines/chemistry , Animals , Cricetinae , Receptors, Opioid/metabolism , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
A series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues have been discovered as novel NOP receptor agonists. Structure-activity relationships have been explored via N-3 substitution of the benzimidazol-2-one with a range of functionality. The N-methyl acetamide derivative (+)-7f was found to be a high-affinity, potent NOP agonist with greater than 100-fold selectivity over the MOP receptor. Furthermore (+)-7f was shown to be both antinociceptive and sedative when administered iv to rodents.
Subject(s)
Analgesics/chemical synthesis , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Hypnotics and Sedatives/chemical synthesis , Receptors, Opioid/agonists , Animals , Rodentia , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified.
Subject(s)
Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Opioid/agonists , Animals , CHO Cells , Cricetinae , Cyclic AMP/biosynthesis , Drug Design , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Male , Mice , Structure-Activity Relationship , Transfection , Vas Deferens , Nociceptin ReceptorSubject(s)
Androstanols/chemistry , Cyclodextrins/chemistry , Neuromuscular Blockade , Neuromuscular Nondepolarizing Agents/chemistry , gamma-Cyclodextrins , Androstanols/pharmacology , Animals , Crystallography, X-Ray , Cyclodextrins/pharmacology , Diaphragm/drug effects , Diaphragm/innervation , In Vitro Techniques , Macaca mulatta , Mice , Models, Molecular , Muscle Contraction/drug effects , Neuromuscular Nondepolarizing Agents/pharmacology , Rocuronium , SugammadexABSTRACT
A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.
