ABSTRACT
Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on â¼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Chromatography, Liquid , Mass Spectrometry , Proton Magnetic Resonance SpectroscopyABSTRACT
The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human ß3-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR studies directed towards maintaining well established ß3 potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed.
Subject(s)
Adrenergic beta-3 Receptor Agonists/pharmacology , Piperazines/pharmacology , Urinary Bladder, Overactive/drug therapy , Adrenergic beta-3 Receptor Agonists/chemistry , Adrenergic beta-3 Receptor Agonists/therapeutic use , Humans , Piperazines/chemistry , Piperazines/therapeutic use , Structure-Activity RelationshipABSTRACT
The discovery of vibegron, a potent and selective human ß3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical ß3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived ß3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.
Subject(s)
Adrenergic beta-3 Receptor Agonists/therapeutic use , Pyrimidinones/therapeutic use , Pyrrolidines/therapeutic use , Urinary Bladder, Overactive/drug therapy , Adrenergic beta-3 Receptor Agonists/pharmacokinetics , Adrenergic beta-3 Receptor Agonists/toxicity , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Discovery , Female , Humans , Lipidoses/chemically induced , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Models, Molecular , Pyrimidinones/pharmacokinetics , Pyrimidinones/toxicity , Pyrrolidines/pharmacokinetics , Pyrrolidines/toxicity , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, beta/drug effects , Receptors, Adrenergic, beta/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Structure-Activity Relationship , Urinary Bladder/drug effects , Urination/drug effects , X-Ray DiffractionABSTRACT
A series of conformationally restricted acetanilides were synthesized and evaluated as ß3-adrenergic receptor agonists (ß3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine ß3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent ß3-AR mediated responses in a rat bladder hyperactivity model.
Subject(s)
Acetanilides/chemical synthesis , Acetanilides/pharmacology , Adrenergic beta-3 Receptor Agonists/chemical synthesis , Adrenergic beta-3 Receptor Agonists/pharmacology , Urinary Bladder, Overactive/drug therapy , Acetanilides/therapeutic use , Adrenergic beta-3 Receptor Agonists/therapeutic use , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Design , Humans , Magnetic Resonance Spectroscopy , Molecular ConformationABSTRACT
INTRODUCTION: The Diver Emergency Service (DES) in Australia provides specialised medical advice on diving incidents 24 hours a day to divers, dive operators, families and health professionals. It is operated from the Hyperbaric Medicine Unit of the Royal Adelaide Hospital where the physician-on-call also carries the DES phone (1800-088200 or +61-8-8212-9242). METHODS: Data from calls to the service have been compiled into a computer database since 1991. Calls for the 17 years from 1991 through 2007 were analysed. RESULTS: A total of 6,083 calls were logged, an average of 358 calls a year. Calls from Queensland and New South Wales each accounted for 25% of calls. Calls originating from outside Australia have been increasing and now make up 25% of calls. The diver themselves initiated the call 50% of the time and 66% of the calls were about male divers. The age range of divers was 12 to 95 years old. The mean age has increased from 30 to 36 years, with a greater proportion of calls from divers aged 50 years or older (from 2% to 14%). The largest group of calls (37%) related to whether symptoms might be the result of decompression illness (DCI). DCI was considered to be the probable diagnosis in 17% of calls, and possible in a further 12%. Other common findings were barotrauma (11%) and questions regarding fitness to dive (15%). Older divers were more likely to call in relation to a medical problem. CONCLUSION: Interpretation of these data is qualitative but the prolonged collection period of 17 years allows some consideration of trends as to who calls the DES and why.
Subject(s)
Decompression Sickness/diagnosis , Diving/statistics & numerical data , Emergency Medical Services/statistics & numerical data , Hotlines/statistics & numerical data , Adolescent , Adult , Age Distribution , Age Factors , Aged , Aged, 80 and over , Australia/epidemiology , Barotrauma/diagnosis , Barotrauma/epidemiology , Child , Decompression Sickness/epidemiology , Female , Humans , Male , Middle Aged , Remote Consultation/statistics & numerical data , Sex Distribution , Young AdultABSTRACT
A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.
Subject(s)
Acetamides/pharmacology , Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Antagonists/pharmacology , Benzamides/pharmacology , Acetamides/pharmacokinetics , Adrenergic beta-Antagonists/pharmacokinetics , Animals , Benzamides/pharmacokinetics , Rodentia , Structure-Activity RelationshipABSTRACT
This Letter describes optimization of ghrelin receptor antagonists and inverse agonists starting from a screening hit.
Subject(s)
Anti-Obesity Agents/chemistry , Receptors, Ghrelin/antagonists & inhibitors , Sulfonamides/chemistry , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Cell Line , Drug Design , Drug Inverse Agonism , Humans , Male , Obesity/drug therapy , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , BenzenesulfonamidesABSTRACT
A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.
Subject(s)
Chemistry, Pharmaceutical/methods , Receptors, CCR2/antagonists & inhibitors , Receptors, CCR2/chemistry , Administration, Oral , Animals , Chemotaxis , Dogs , Drug Design , Humans , Inhibitory Concentration 50 , Macaca mulatta , Models, Chemical , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold.
Subject(s)
Cyclopentanes/chemistry , Receptors, CCR2/antagonists & inhibitors , Spiro Compounds/chemistry , Acetals/chemistry , Acetals/pharmacology , Crystallography, X-Ray , Cyclopentanes/pharmacology , Humans , Kinetics , Molecular Conformation , Monocytes/drug effects , Monocytes/metabolism , Receptors, CCR2/metabolism , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
This report describes replacement of the 4-(4-fluorophenyl)piperidine moiety in our CCR2 antagonists with 4-heteroaryl piperidine and 4-(carboxyphenyl)-piperidine subunits. Some of the resulting analogs retained potency in our CCR2 binding assay and had improved selectivity versus the I(Kr) channel; poor selectivity against I(Kr) had been a liability of earlier analogs in this series.