ABSTRACT
Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H(1)-antihistamines. Reductions in pK(a) via incorporation of a ß-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.
Subject(s)
Cytochrome P-450 CYP2D6/chemistry , Histamine H1 Antagonists/chemistry , Indenes/chemistry , Pyrazines/chemistry , Receptors, Histamine H1/chemistry , Biotransformation , Cytochrome P-450 CYP2D6/metabolism , Histamine H1 Antagonists/chemical synthesis , Histamine H1 Antagonists/pharmacokinetics , Indenes/chemical synthesis , Indenes/pharmacokinetics , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Receptors, Histamine H1/metabolism , Structure-Activity RelationshipABSTRACT
Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.
Subject(s)
Histamine H1 Antagonists/chemistry , Indenes/chemistry , Pyridazines/chemistry , Receptors, Histamine H1/chemistry , Sleep Initiation and Maintenance Disorders/drug therapy , Animals , Cytochrome P-450 CYP2D6/metabolism , Dimethindene/chemistry , Electroencephalography , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/therapeutic use , Humans , Indenes/pharmacokinetics , Indenes/therapeutic use , Microsomes, Liver/metabolism , Models, Animal , Pyridazines/pharmacokinetics , Pyridazines/therapeutic use , Rats , Receptors, Histamine H1/metabolism , Structure-Activity RelationshipABSTRACT
A series of indene analogs of the H(1)-antihistamine (-)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H(1)-antihistamines with desirable selectivity over CYP enzymes, the M(1) muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.
Subject(s)
Histamine Antagonists/therapeutic use , Indenes/therapeutic use , Sleep Initiation and Maintenance Disorders/drug therapy , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Humans , Indenes/chemistry , Indenes/pharmacologyABSTRACT
A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H(1)-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H(1)-antihistamines.
Subject(s)
Benzimidazoles/chemistry , Central Nervous System/drug effects , Histamine H1 Antagonists/chemistry , Sleep Initiation and Maintenance Disorders/drug therapy , Benzimidazoles/chemical synthesis , Benzimidazoles/therapeutic use , Drug Discovery , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Histamine H1 Antagonists/chemical synthesis , Histamine H1 Antagonists/therapeutic use , Humans , Structure-Activity RelationshipABSTRACT
Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
Subject(s)
Histamine H1 Antagonists/pharmacology , Histamine H1 Antagonists/therapeutic use , Sleep Initiation and Maintenance Disorders/drug therapy , Animals , Brain/metabolism , Dimethindene/metabolism , Dimethindene/pharmacokinetics , Dimethindene/pharmacology , Dimethindene/therapeutic use , Electroencephalography/drug effects , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Histamine H1 Antagonists/metabolism , Histamine H1 Antagonists/pharmacokinetics , Humans , Rats , Receptors, Muscarinic/metabolism , Sleep/drug effects , Substrate SpecificityABSTRACT
The benzimidazole core of the selective non-brain-penetrating H(1)-antihistamine mizolastine was used to identify a series of brain-penetrating H(1)-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain-penetrating H(1)-antihistamines were identified and in vivo efficacy was demonstrated in a rat EEG/EMG model. Further optimization focused on strategies to attenuate an identified hERG liability, leading to the discovery of 4i with a promising in vitro profile.
Subject(s)
Benzimidazoles/antagonists & inhibitors , Benzimidazoles/chemistry , Brain/drug effects , Chemistry, Pharmaceutical/methods , Histamine Antagonists/chemical synthesis , Histamine Antagonists/pharmacology , Sleep Initiation and Maintenance Disorders/drug therapy , Animals , Drug Design , ERG1 Potassium Channel , Electroencephalography/methods , Electromyography/methods , Ether-A-Go-Go Potassium Channels/chemistry , Humans , Models, Chemical , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Antagonists of the corticotropin-releasing factor (CRF) neuropeptide should prove to be effective in treating stress and anxiety-related disorders. In an effort to identify antagonists with improved physicochemical properties, new tricyclic CRF(1) antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF(1) binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pK(i) value of 8.5. Compound 12a proved to be a functional CRF(1) antagonist with pIC(50) values of 7.1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Acenaphthenes , Adrenocorticotropic Hormone/biosynthesis , Animals , Cells, Cultured , Corticotropin-Releasing Hormone/metabolism , Cyclic AMP/biosynthesis , Drug Design , Female , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Molecular Conformation , Pituitary Gland, Anterior/cytology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF(1)) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF(1) antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.
