ABSTRACT
As part of a medicinal chemistry program aimed at developing a highly potent and selective cathepsin C inhibitor, tritium, carbon-14, and stable isotope-labeled materials were required. The synthesis of tritium-labeled methanesulfonate 5 was achieved via catalytic tritiolysis of a chloro precursor, albeit at a low radiochemical purity of 67%. Tritium-labeled AZD5248 was prepared via a 3-stage synthesis, utilizing amide-directed hydrogen isotope exchange. Carbon-14 and stable isotope-labeled AZD5248 were successfully prepared through modifications of the medicinal chemistry synthetic route, enabling the use of available labeled intermediates.
Subject(s)
Biphenyl Compounds/chemistry , Cathepsin C/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Tritium/chemistry , Carbon Radioisotopes/chemistry , Cysteine Proteinase Inhibitors/chemistry , Mesylates/chemistry , Radiopharmaceuticals/chemistryABSTRACT
The CXCR2 antagonist AZD5069 has been synthesized in tritium and carbon-14-labelled forms. [(3) H]AZD5069 was prepared via reductive dehalogenation of an iodinated precursor with tritium gas to provide material with a specific activity of 25.1 Ci/mmol. [(14) C]AZD5069 was labelled in the pyrimidine ring from [(14) C]thiourea in an overall radiochemical yield of 18%. In addition, a synthetic route to the major metabolite of AZD5069 was developed. The synthesis of this metabolite was achieved from AZD5069 using a chemoselective Lindgren-Pinnick reaction in order to minimize oxidation of the sulphide group.
Subject(s)
Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Receptors, Interleukin-8B/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfonamides/metabolism , Carbon Radioisotopes/chemistry , Chemistry Techniques, Synthetic , Humans , Isotope Labeling , Pyrimidines/chemistry , Pyrimidines/pharmacology , Radiochemistry , Sulfonamides/chemistry , Sulfonamides/pharmacology , Tritium/chemistryABSTRACT
The discovery and optimisation of a series of zwitterionic CCR3 antagonists is described. Optimisation of the structure led to AZ12436092, a compound with excellent selectivity over activity at hERG and outstanding pharmacokinetics in preclinical species.
Subject(s)
Drug Discovery , Piperidines/chemistry , Piperidines/pharmacokinetics , Receptors, CCR3/antagonists & inhibitors , Animals , Humans , Inhibitory Concentration 50 , Molecular Structure , RatsABSTRACT
Muscle atrophy and cachexia are common comorbidities among patients suffering from cancer, chronic obstructive pulmonary disease, and several other chronic diseases. The peptide hormone ghrelin exerts pleiotropic effects including the stimulation of growth hormone secretion and subsequent increase of insulin-like growth factor-1 levels, an important mediator of muscle growth and repair. Ghrelin also acts on inflammation, appetite, and adipogenesis and therefore has been considered a promising therapeutic target for catabolic conditions. We previously reported on the synthesis and properties of an indane based series of ghrelin receptor full agonists which led to a sustained increase of insulin-like growth factor-1 in a dog pharmacodynamic study. Herein we report on the identification of a series of pyrrolidine or piperidine based full agonists and attempted optimization to give compounds with profiles suitable for progression as clinical candidates.
Subject(s)
Drug Design , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Receptors, Ghrelin/agonists , Animals , Dogs , HEK293 Cells , Humans , Pyrrolidines/pharmacokinetics , RatsABSTRACT
Cachexia and muscle wasting are very common among patients suffering from cancer, chronic obstructive pulmonary disease, and other chronic diseases. Ghrelin stimulates growth hormone secretion via the ghrelin receptor, which subsequently leads to increase of IGF-1 plasma levels. The activation of the GH/IGF-1 axis leads to an increase of muscle mass and functional capacity. Ghrelin further acts on inflammation, appetite, and adipogenesis and for this reason was considered an important target to address catabolic conditions. We report the synthesis and properties of an indane based series of ghrelin receptor full agonists; they have been shown to generate a sustained increase of IGF-1 levels in dog and have been thoroughly investigated with respect to their functional activity.
Subject(s)
Indans/chemistry , Indans/pharmacology , Receptors, Ghrelin/agonists , Animals , HEK293 Cells , Humans , Indans/pharmacokinetics , Male , Models, Molecular , Protein Conformation , Rats , Receptors, Ghrelin/chemistryABSTRACT
A novel series of antagonists of the human P2X7 receptor is described. Modification of substituents enabled identification of compounds selective for the rat P2X7 receptor and provides useful pharmacological tools for evaluation of the role of P2X7 in disease.