ABSTRACT
A novel series of quinolones was discovered as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) using a structure-based approach. The lead quinolones exhibited single digit nanomolar potency in the HIV-1 replication assays. The preliminary SAR of these quinolones was also established via systematic structural modifications. These novel and potent quinolones could serve as advanced leads for further optimization.
Subject(s)
Reverse Transcriptase Inhibitors/pharmacology , Binding Sites , Drug Resistance, Viral , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/metabolism , Models, Chemical , Models, Molecular , Mutation , Quinolones/chemistry , Structure-Activity Relationship , Virus ReplicationABSTRACT
The synthesis and preliminary structure-activity relationship of a series of pyrrolidinones are described. These pyrrolidinones have been characterized as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) which are highly potent against wild-type and drug-resistant human immunodeficiency viruses (HIV-1).
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV-1/drug effects , Pyrrolidinones/chemical synthesis , Pyrrolidinones/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Humans , Microbial Sensitivity Tests , Molecular Structure , Pyrrolidinones/chemistry , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Development of alphavbeta3-integrin inhibitors has been hampered by a lack of pharmacodynamic endpoints to identify doses that inhibit alphavbeta3 in vivo. To address this need, we developed an alphavbeta3 radioreceptor assay (RRA) that could be performed in 100% plasma. The RRA was based on 125I-echistatin binding to plate-immobilized alphavbeta3. Small molecule alphavbeta3 inhibitors efficiently competed echistatin binding to alphavbeta3 when the assay was carried out in buffer. However, when carried out in 100% plasma, the RRA revealed a 45 to >3000-fold loss in compound potencies. The losses in potency reflected, in part, the high plasma protein binding by the compounds examined. The RRA was adapted as an ex vivo pharmacodynamic model. Echistatin binding was measured in the presence of plasma harvested at timed intervals from rats dosed with select compounds. Using this pharmacodynamic model, compound and dose selection was optimized for further testing in models of corneal angiogenesis. Moderate anti-angiogenic activity was achieved when rats were dosed sufficient to achieve sustained (>50%) plasma inhibition through the trough interval. Thus, the RRA provided a simple technique to rank order compound potency in plasma, and could find general use as an ex vivo pharmacodynamic assay to select compounds and doses for preclinical and clinical proof-of-principle studies.
Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Integrin alphaVbeta3/blood , Radioligand Assay/methods , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Blood Platelets/drug effects , Blood Platelets/metabolism , Blood Proteins/metabolism , Cornea/blood supply , Cornea/drug effects , Drug Evaluation, Preclinical , In Vitro Techniques , Intercellular Signaling Peptides and Proteins , Male , Neovascularization, Pathologic/prevention & control , Peptides/blood , Peptides/pharmacokinetics , Protein Binding , Rats , Rats, Sprague-DawleyABSTRACT
We describe the synthesis and structure/activity relationship of RGD mimetics that are potent inhibitors of the integrin alpha(v)beta3. Indol-1-yl propionic acids containing a variety of basic moieties at the 5-position, as well as substitutions alpha and beta to the carboxy terminus were synthesized and evaluated. Novel compounds with improved potency have been identified.
Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Propionates/pharmacology , Indoles/chemistry , Molecular Mimicry , Oligopeptides/chemistry , Propionates/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of potent and selective alpha(v)beta(3)/alpha(v)beta(5) dual( )()inhibitors was designed, synthesized, and evaluated against several integrins. These compounds were synthesized through a Mitsunobu reaction between the guanidinium mimetics and the corresponding central templates. Guanidinium mimetics with enhaced rigidity (i.e., (2-pyridylamino)propoxy versus the 2-(6-methylamino-2-pyridyl)ethoxy) led to improved activity toward alpha(v)beta(3). Exemplary oral bioavailability in mice was achieved using the indole central scaffold. Although, oral bioavailability was maintained when the indole molecular core was replace with the bioisosteric benzofuran or benzothiophene ring systems, it was found to not significantly impact the integrin activity or selectivity. However, the indole series displayed the best in vivo pharmacokinetic properties. Thus, the indole series was selected for further structure-activity relationships to obtain more potent alpha(v)beta(3)/alpha(v)beta(5) dual antagonist with improved oral bioavailability.
