ABSTRACT
A series of potent, selective and long-acting quinoline-based sulfonamide human H1 histamine receptor antagonists, designed for once-daily intranasal administration for the treatment of rhinitis were developed. Sulfonamide 33b had a slightly lower affinity for the H1 receptor than azelastine, had low oral bioavailability in the rat and dog, and was turned over to five major metabolites. Furthermore, 33b had longer duration of action than azelastine in guinea pigs, lower rat brain-penetration, and did not cause time dependent inhibition of CYP2D6 or CYP3A4. The clinical dose in humans is expected to be low (approximately 0.5mg per day) based on the clinical dose used for azelastine and a comparison of efficacy data from animal models for 33b and azelastine.
Subject(s)
Histamine H1 Antagonists/chemistry , Quinolines/chemistry , Receptors, Histamine H1/metabolism , Rhinitis, Allergic/drug therapy , Sulfanilamides/chemistry , Sulfonamides/chemistry , Sulfones/chemistry , Administration, Intranasal , Animals , Brain/metabolism , Dogs , Guinea Pigs , Half-Life , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/therapeutic use , Inhibitory Concentration 50 , Quinolines/pharmacokinetics , Quinolines/therapeutic use , Rats , Receptors, Histamine H1/chemistry , Rhinitis, Allergic/metabolism , Rhinitis, Allergic/pathology , Structure-Activity Relationship , Sulfanilamide , Sulfanilamides/pharmacokinetics , Sulfanilamides/therapeutic use , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use , Sulfones/pharmacokinetics , Sulfones/therapeutic useABSTRACT
The synthesis of potent amide-containing phthalazinone H1 histamine receptor antagonists is described. Three analogues 3e, 3g, and 9g were equipotent with azelastine and were longer-acting in vitro. Amide 3g had low oral bioavailability, low brain-penetration, high metabolic clearance, and long duration of action in vivo, and it was suitable for once-daily dosing intranasally, with a predicted dose for humans of approximately 0.5 mg per day.
ABSTRACT
A novel series of potent quinoline-based human H1 and H3 bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1 potency (pA2 8.8 vs 9.7 for the clinical goldstandard azelastine), and H3 potency (pKi 9.1vs 6.8 for azelastine), better selectivity over α1A, α1B and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.
Subject(s)
Drug Discovery , Histamine H1 Antagonists/pharmacology , Histamine H3 Antagonists/pharmacology , Quinolines/pharmacology , Receptors, Histamine H1/metabolism , Receptors, Histamine H3/metabolism , Dose-Response Relationship, Drug , Histamine H1 Antagonists/chemical synthesis , Histamine H1 Antagonists/chemistry , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/chemistry , Humans , Ligands , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
A series of novel, potent, and selective human ß2 adrenoceptor agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol is presented. Sulfone 10b had salmeterol-like potency and selectivity profile, long duration of action on guinea pig trachea, and longer than salmeterol duration of action in vivo, suitable for once-daily dosing. It had lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes. It was metabolized in human hepatocytes by hydroxylation, oxidation, cleavage, and conjugation; most of the metabolites would be expected to have reduced or no ß2 activity. The 4-biphenylsulfonic acid was identified as a crystalline, non-hygroscopic salt of 10b, suitable for inhaled delivery. Furthermore, it was free of any genetic toxicity issues and was considered as a backup to vilanterol.
Subject(s)
Adrenergic beta-2 Receptor Agonists/chemical synthesis , Sulfones/chemical synthesis , Adrenergic beta-2 Receptor Agonists/metabolism , Adrenergic beta-2 Receptor Agonists/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Drug Administration Schedule , Drug Discovery , Guinea Pigs , Hepatocytes/metabolism , Humans , Rats , Sulfones/metabolism , Sulfones/pharmacology , Trachea/drug effectsABSTRACT
A series of novel, potent and selective human ß(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
Subject(s)
Adrenergic beta-2 Receptor Agonists/chemical synthesis , Asthenia/drug therapy , Bronchodilator Agents/pharmacology , Urea/analogs & derivatives , Urea/pharmacology , Adrenergic beta-2 Receptor Agonists/chemistry , Adrenergic beta-2 Receptor Agonists/pharmacokinetics , Adrenergic beta-2 Receptor Agonists/pharmacology , Albuterol/analogs & derivatives , Albuterol/chemistry , Albuterol/pharmacokinetics , Albuterol/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Dose-Response Relationship, Drug , Female , Guinea Pigs , Humans , Male , Rats , Salmeterol Xinafoate , StereoisomerismABSTRACT
A series of novel, potent and selective human ß(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 µM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m.
Subject(s)
Adrenergic beta-2 Receptor Agonists/chemical synthesis , Drug Discovery , Hydantoins/chemistry , Uracil/chemistry , Adrenergic beta-2 Receptor Agonists/metabolism , Adrenergic beta-2 Receptor Agonists/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Dose-Response Relationship, Drug , Female , Guinea Pigs , Hepatocytes/chemistry , Hepatocytes/metabolism , Humans , Male , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Rats , Rats, Wistar , Receptors, Adrenergic, beta-2/metabolism , Stereoisomerism , Trachea/drug effectsABSTRACT
A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.
Subject(s)
Drug Discovery/methods , Phthalazines/administration & dosage , Phthalazines/pharmacology , Receptors, Histamine H1/metabolism , Receptors, Histamine H3/metabolism , Rhinitis/drug therapy , Administration, Intranasal , Administration, Oral , Histamine H1 Antagonists/administration & dosage , Histamine H1 Antagonists/chemistry , Histamine H1 Antagonists/pharmacology , Histamine H1 Antagonists/therapeutic use , Histamine H3 Antagonists/administration & dosage , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/pharmacology , Histamine H3 Antagonists/therapeutic use , Humans , Models, Molecular , Phthalazines/chemistry , Phthalazines/therapeutic use , Protein Conformation , Receptors, Histamine H1/chemistryABSTRACT
A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.
Subject(s)
Adrenergic beta-2 Receptor Agonists , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Adrenergic beta-Agonists/chemical synthesis , Adrenergic beta-Agonists/metabolism , Animals , Benzyl Alcohol/chemistry , Benzyl Alcohols/chemical synthesis , Benzyl Alcohols/chemistry , Benzyl Alcohols/metabolism , Benzyl Alcohols/pharmacology , CHO Cells , Chlorobenzenes/chemical synthesis , Chlorobenzenes/chemistry , Chlorobenzenes/metabolism , Chlorobenzenes/pharmacology , Cricetinae , Cricetulus , Humans , Models, Molecular , Protein Conformation , Rats , Receptors, Adrenergic, beta-2/chemistry , Structure-Activity RelationshipABSTRACT
A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.
Subject(s)
2-Hydroxyphenethylamine/analogs & derivatives , Adrenergic beta-2 Receptor Agonists , Sulfonamides/chemical synthesis , 2-Hydroxyphenethylamine/chemical synthesis , 2-Hydroxyphenethylamine/chemistry , 2-Hydroxyphenethylamine/pharmacology , Administration, Oral , Albuterol/analogs & derivatives , Albuterol/chemistry , Albuterol/pharmacology , Animals , Biological Availability , Bronchi/drug effects , Bronchi/physiology , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/biosynthesis , Dogs , Guinea Pigs , Humans , In Vitro Techniques , Microsomes/metabolism , Models, Molecular , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Rats , Salmeterol Xinafoate , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Trachea/drug effects , Trachea/physiologyABSTRACT
A series of ketopiperazines were prepared and evaluated for their activity as histamine H 3 antagonists. From investigation of the tertiary basic center in the aminopropyloxyphenyl template, the 2( R)-methylpyrrolidine was identified as the most potent amine. In the more rigid piperidineoxyphenyl template the N-cyclobutyl group was the most potent amine. The 4-fluorobenzyol, 4-cyanobenzoyl, and 2,4-difluorobenzoyl groups provided good pharmacokinetic profiles for the various amides. The PSA and log D values of these compounds suggested low brain penetration. The compounds had very high selectivity over other receptors and did not inhibit hepatic cytochrome P450, indicating low drug-drug interaction potential. Compound 22i was identified as the best compound of this series based on its overall profile of high potency, selectivity, low brain penetration, lack of CYP450 inhibition, high oral bioavailability, and pharmacokinetic properties.
