ABSTRACT
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
Among the FDA approved drugs for the treatment of AIDS, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of first-line anti-HIV-1 therapy because of the less-severe adverse effects associated with NNRTIs administration in comparison to therapies based on other anti-HIV-1 agents. In this contest, 3,4-dihydro-2-alkoxy-6-benzyl-4-oxypyrimidines (DABOs) have been the object of many studies aimed at identifying novel analogues endowed with potent inhibitory activity towards HIV-1 wild type and especially drug-resistant mutants. Accordingly, based on the encouraging results obtained from the biological screening of our internal collection of S-DABO derivatives, we started with the systematic functionalization of the pyrimidine scaffold to identify the minimal required structural features for RT inhibition. Herein, we describe how the combination of synthetic, biological, and molecular modeling studies led to the identification of two novel subclasses of S-DABO analogues: S-DABO cytosine analogues (S-DABOCs) and 4-dimethyamino-6-vinylpyrimidines (DAVPs).
Subject(s)
Drug Design , HIV-1/drug effects , Reverse Transcriptase Inhibitors/chemical synthesis , HIV Reverse Transcriptase/genetics , HIV-1/genetics , Humans , Mutation , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A series of novel S-DABO analogues, characterized by different substitution patterns at positions 2, 5, and 6 of the heterocyclic ring, were synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Most of the compounds proved to be highly active on the wild-type enzyme both in enzymatic and cellular assays, with one of them emerging as the most active reverse transcriptase inhibitor reported so far (EC50wt=25 pM). The general loss of potency displayed by the compounds toward clinically relevant mutant strains was deeply studied through a molecular modeling approach, leading to the evidence that the dynamic of the entrance in the non-nucleoside binding pocket could represent the basis of the inhibitory activity of the molecules.
Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , Pyrimidines/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Sulfides/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Cell Line , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/genetics , HIV-1/enzymology , Humans , Models, Molecular , Mutation , Pyrimidines/chemistry , Pyrimidines/pharmacology , Quantitative Structure-Activity Relationship , Recombinant Proteins/chemistry , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Sulfides/chemistry , Sulfides/pharmacologyABSTRACT
A simple and efficient methodology for the parallel solution-phase synthesis has been set up to obtain a series of thiouracils, in turn selectively S-benzylated under microwave irradiation to give new S-DABOs. Biological screening led to the identification of compounds with nanomolar activity toward both the highly purified recombinant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) enzyme (wild-type and mutants) and wild-type (wt) and mutant HIV-1 strains. In particular, 20 was found to be the most potent S-DABO reported so far (ID50 = 26 nM toward the isolated wt enzyme) with subnanomolar activity toward both the wt and the pluriresistant virus (IRLL98) HIV-1 strain (EC50 < 0.14 nM and EC50 = 0.22 nM, respectively). Molecular modeling calculations were also performed to investigate the binding mode of such compounds onto the non-nucleoside reverse transcriptase inhibitor binding site and to rationalize the relationships between their chemical structure and activity values toward wt RT.
