ABSTRACT
Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts, no new antibiotic class with activity against Gram-negative bacteria has been approved in over 50 years. LepB inhibitors (LepBi) based on the arylomycin class of natural products are a novel class of antibiotics and function by inhibiting the bacterial type I signal peptidase (SPase) in Gram-negative bacteria. One critical aspect of LepBi development involves optimization of the membrane-anchored lipophilic portion of the molecule. We therefore developed an approach that assesses the effect of this portion on the complicated equilibria of plasma protein binding, crossing the outer membrane of Gram-negative bacteria and anchoring in the bacterial inner membrane to facilitate SPase binding. Our findings provide important insights into the development of antibacterial agents where the target is associated with the inner membrane of Gram-negative bacteria.
ABSTRACT
Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins-a class of natural products with weak activity and limited spectrum-to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.
Subject(s)
Anti-Bacterial Agents/classification , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Peptides, Cyclic/pharmacology , Biocatalysis/drug effects , Biological Products/classification , Biological Products/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Escherichia coli/enzymology , Gram-Negative Bacteria/enzymology , Gram-Negative Bacteria/pathogenicity , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/microbiology , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/enzymology , Klebsiella pneumoniae/pathogenicity , Lysine/metabolism , Membrane Proteins/antagonists & inhibitors , Microbial Sensitivity Tests , Peptides, Cyclic/chemistry , Porins , Protein Binding , Protein Domains , Serine Endopeptidases , Substrate SpecificityABSTRACT
Continuing studies based on dihydroquinoline glucocorticoid receptor agonists lead to the discovery of a series of C4-oxime analogs. Representative compounds exhibited potent transrepression activity with minimal transactivation of phosphoenolpyruvate caboxykinase (PEPCK), a key protein in the gluconeogenesis pathway. These compounds represent promising leads in identifying GR agonists with high anti-inflammatory activity and attenuated potential for glucose elevation.
Subject(s)
Carboxy-Lyases/metabolism , Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Enzyme Activation , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
Continuing studies on tetrahydroquinoline glucocorticoid receptor anti-inflammatory agents lead to the identification of several tetrahydroquinolin-3-yl carbamates that exhibited steroid-like activity in in vitro transrepression assays with reduced transactivation of phosphoenol pyruvate carboxykinase (PEPCK), a key enzyme in the gluconeogenesis pathway.
Subject(s)
Carboxy-Lyases/metabolism , Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Enzyme ActivationABSTRACT
A series of tetrahydroquinoline derivatives were synthesized and profiled for their ability to act as glucocorticoid receptor selective modulators. Structure-activity relationships of the tetrahydroquinoline B-ring lead to the discovery of orally available GR-selective agonists with high in vivo activity.
Subject(s)
Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Administration, Oral , Animals , Drug Discovery , Enzyme-Linked Immunosorbent Assay , Humans , Quinolines/administration & dosage , Quinolines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We have previously disclosed a series of glucocorticoid receptor (GR) ligands derived from 6-indole-1,2,3,4-tetrahydroquinolines through structure-activity relationship (SAR) of the pendent C6-indole ring. In parallel with this effort, we now report SAR of the tetrahydroquinoline A-ring that identified the importance of a C3 hydroxyl in improving GR selectivity within a series of non-steroidal GR agonists.
Subject(s)
Quinolines/chemistry , Receptors, Glucocorticoid/agonists , Drug Evaluation, Preclinical , Protein Binding , Quinolines/chemical synthesis , Quinolines/pharmacology , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
Steroidal glucocorticoids are widely prescribed for the treatment of a variety of inflammatory and autoimmune diseases. Although they are effective, the side-effects associated with chronic glucocorticoid treatment, such as osteoporosis and hyperglycemia, can severely limit their long-term use. Hence, there is a need to develop new effective anti-inflammatory agents for systemic use which are dissociated from their unwanted side effects.
Subject(s)
Anti-Inflammatory Agents/chemistry , Receptors, Glucocorticoid/drug effects , Drug Design , Glucocorticoids/chemistry , Humans , Ligands , Structure-Activity RelationshipABSTRACT
A series of nonsteroidal glucocorticoid receptor (GR) ligands based on a 6-indole-1,2,3,4-tetrahydroquinoline scaffold are reported. Structure-activity relationship (SAR) of the pendent indole group identified compound 20 exhibiting good GR binding affinity (K(i)=1.5nM) and 100- to 1000-fold selectivity over MR, PR, and AR while showing activity in an E-selectin repression assay.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Indoles/pharmacology , Quinolines/pharmacology , Receptors, Glucocorticoid/drug effects , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Binding Sites , Drug Evaluation, Preclinical , Indoles/chemical synthesis , Indoles/chemistry , Ligands , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Modification on a lead series of [1,4]oxazino[3,2-g]quinolin-7-ones at the 2-position led to selective androgen receptor modulators with improved in vivo activity. The most potent analog (-)-33a exhibited full maintenance of levator ani muscle at 3mg/kg and reduced activity on ventral prostate weight in a 2-week orally-dosed and orchidectomized rat maintenance assay.
Subject(s)
Anabolic Agents/pharmacology , Oxazines/pharmacology , Prostate/drug effects , Quinolones/pharmacology , Receptors, Androgen , Administration, Oral , Anabolic Agents/chemical synthesis , Androgen Receptor Antagonists , Androgens , Animals , Male , Models, Chemical , Orchiectomy , Organ Size/drug effects , Oxazines/chemical synthesis , Prostate/anatomy & histology , Quinolones/chemical synthesis , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Testosterone/pharmacologyABSTRACT
Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2'-(thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzopyrans/chemical synthesis , Multiple Myeloma/drug therapy , Quinolines/chemical synthesis , Receptors, Glucocorticoid/drug effects , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzopyrans/chemistry , Benzopyrans/pharmacology , Binding, Competitive , Dexamethasone/pharmacology , Humans , Mice , Mineralocorticoid Receptor Antagonists , Models, Molecular , Multiple Myeloma/pathology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Mineralocorticoid/agonists , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A series of androgen receptor modulators based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.
Subject(s)
Oxazines/chemical synthesis , Oxazines/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Receptors, Androgen/drug effects , Animals , Cell Line , Dose-Response Relationship, Drug , Humans , Indicators and Reagents , Male , Models, Molecular , Orchiectomy , Rats , Receptors, Androgen/chemistry , Receptors, Progesterone/chemistry , Receptors, Progesterone/drug effects , Receptors, Somatotropin/chemistry , Receptors, Somatotropin/drug effects , Structure-Activity Relationship , Testosterone/bloodABSTRACT
A series of 5-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-1-aza-6-oxa-chrysenes was synthesized and profiled for their ability to act as selective glucocorticoid receptor modulators (SGRMs). The synthesis and structure-activity relationships for this series of compounds are presented.
Subject(s)
Chrysenes/pharmacology , Receptors, Glucocorticoid/drug effects , Chrysenes/chemical synthesis , Chrysenes/chemistry , Structure-Activity RelationshipABSTRACT
Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.
Subject(s)
Oxazines/chemical synthesis , Quinolones/chemical synthesis , Receptors, Androgen/drug effects , Anabolic Agents/chemical synthesis , Anabolic Agents/chemistry , Anabolic Agents/pharmacology , Androgens , Animals , Binding, Competitive , Cell Line, Tumor , Humans , Male , Muscle, Skeletal/anatomy & histology , Muscle, Skeletal/drug effects , Organ Size/drug effects , Oxazines/chemistry , Oxazines/pharmacology , Prostate/anatomy & histology , Prostate/drug effects , Quinolones/chemistry , Quinolones/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transcriptional Activation/drug effectsABSTRACT
A series of alkylamino-2-quinolinone compounds (3) was discovered as androgen receptor modulators based on an early linear tricyclic quinoline pharmacophore (1). The series demonstrated selective high binding affinity to androgen receptor and potent receptor modulating activities in the cotransfection assays.
