ABSTRACT
A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases. A few derivatives with overall favorable developability characteristics were selected for further late lead optimization studies.
Subject(s)
Heptanes/chemistry , Heptanes/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Animals , CHO Cells , Cricetulus , Crystallography, X-Ray , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Models, Molecular , Receptors, Dopamine D3/metabolism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.
Subject(s)
Pyrroles/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Triazoles/pharmacology , Animals , Binding, Competitive/drug effects , CHO Cells , Cricetulus , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , HEK293 Cells , Humans , Models, Molecular , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Histamine H1 Antagonists/chemical synthesis , Hypnotics and Sedatives/chemical synthesis , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin 5-HT2 Receptor Antagonists/chemical synthesis , Sleep/drug effects , Spiro Compounds/chemical synthesis , Animals , Biological Availability , Brain/metabolism , Cell Line , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Histamine H1 Antagonists/chemistry , Histamine H1 Antagonists/pharmacology , Humans , Hypnotics and Sedatives/chemistry , Hypnotics and Sedatives/pharmacology , Male , Microsomes, Liver/metabolism , Radioligand Assay , Rats , Rats, Sprague-Dawley , Serotonin 5-HT2 Receptor Antagonists/chemistry , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Sleep Wake Disorders/drug therapy , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity RelationshipSubject(s)
Dibenzocycloheptenes/chemical synthesis , Dibenzocycloheptenes/pharmacology , Hypnotics and Sedatives/chemical synthesis , Cyclization , Dibenzocycloheptenes/chemistry , Humans , Hypnotics and Sedatives/chemistry , Hypnotics and Sedatives/pharmacology , Mianserin/analogs & derivatives , Mianserin/chemistry , Mianserin/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
The functional in vitro study of the enantiomers of imidazolines 4-7 highlighted the role played by the nature of the ortho phenyl substituent in determining the preferred α(2C)-AR configuration. Indeed, the (S) enantiomers of 4-6 or (R) enantiomer of 7 behave as eutomers and activate this subtype as full agonists; the corresponding distomers are partial agonists. Because in clinical pain management with opioids α(2C)-AR agonists, devoid of the α(2A)-AR-mediated side effects, may represent an improvement over current therapies with clonidine like drugs, 4 and its enantiomers, showing α(2C)-agonism/α(2A)-antagonism, have been studied in vivo. The data suggest that partial α(2C)-activation is compatible with effective enhancement of morphine analgesia and reduction both of morphine tolerance acquisition and morphine dependence acquisition and expression. On the contrary, full α(2C)-activation appears advantageous in reducing morphine tolerance expression. Interestingly, the biological profile displayed by 4 (allyphenyline) and its eutomer (S)-(+)-4 has been found to be very unusual.
