Paul L. Feldman

CNS 7056: a novel ultra-short-acting Benzodiazepine.

Background:A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This goal has been achieved by rendering the compound susceptible to metabolism via esterases. The authors now report on the profile of CNS 7056 in vitro and in vivo. Methods:The affinity of CNS 7056 and its carboxylic acid metabolite, CNS 7054, for benzodiazepine receptors and their selectivity profiles were evaluated using radioligand binding. The activity of CNS 7056 and midazolam at subtypes (α1β2γ2, α2β2γ2, α3β2γ2, α5β2γ2) of the γ-aminobutyric acid type A (GABAA) receptor was evaluated using the whole cell patch clamp technique. The activity of CNS 7056 at brain benzodiazepine receptors in vivo was measured in rats using extracellular electrophysiology in the substantia nigra pars reticulata. The sedative profile was measured in rodents using the loss of righting reflex test. Results:CNS 7056 bound to brain benzodiazepine sites with high affinity. The carboxylic acid metabolite, CNS 7054, showed around 300 times lower affinity. CNS 7056 and CNS 7054 (10 μm) showed no affinity for a range of other receptors. CNS 7056 enhanced GABA currents in cells stably transfected with subtypes of the GABAA receptor. CNS 7056, like midazolam and other classic benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor. CNS 7056 (intravenous) caused a dose-dependent inhibition of substantia nigra pars reticulata neuronal firing and recovery to baseline firing rates was reached rapidly. CNS 7056 (intravenous) induced loss of the righting reflex in rodents. The duration of loss of righting reflex was short (< 10 min) and was inhibited by pretreatment with flumazenil. Conclusions:CNS 7065 is a high-affinity and selective ligand for the benzodiazepine site on the GABAA receptor. CNS 7056 does not show selectivity between GABAA receptor subtypes. CNS 7056 is a potent sedative in rodents with a short duration of action. Inhibition of substantia nigra pars reticulata firing and the inhibition of the effects of CNS 7056 by flumazenil show that it acts at the brain benzodiazepine receptor.

Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium.

BackgroundNo replacement for succinylcholine is yet available. GW280430A (AV430A) is a representative of a new class of nondepolarizing neuromuscular blocking drugs called asymmetric mixed-onium chlorofumarates. It undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction, resulting in a very short duration of effect. The neuromuscular, cardiovascular, and autonomic pharmacology of GW280430A is compared herein with that of mivacurium. MethodsAdult male rhesus monkeys and adult male cats were anesthetized with nitrous oxide–oxygen–halothane and chloralose–pentobarbital, respectively. The neuromuscular blocking properties of GW280430A and mivacurium were compared at a stimulation rate of 0.15 Hz in the extensor digitorum of the foot (monkey) and the tibialis anterior (cat). Sympathetic responses were assayed in the cat in the nictitating membrane preparation, and vagal effects were evaluated in the cat via observation of bradycardic responses after stimulation of the cervical right vagus nerve. ResultsGW280430A and mivacurium were equipotent in the monkey (ED95 was 0.06 mg/kg in each case). GW280430A was half as potent as mivacurium in the cat. The total duration of action of GW280430A was less than half that of mivacurium in the monkey; recovery slopes were more than twice as rapid. The 25–75% recovery index of GW280430A did not vary significantly after various bolus doses or infusions, averaging 1.4–1.8 min in the monkey, significantly shorter than the same time interval (4.8–5.7 min) for mivacurium. Dose ratios for autonomic versus neuromuscular blocking properties in the cat were greater than 25 for both GW280430A and mivacurium. The ratio ED Hist:ED95 Neuromuscular Block in the monkey was significantly greater (approximately 53 vs. 13) for GW280430A, indicating approximately four times less relative prominence of the side effects of skin flushing and decrease of blood pressure, which are associated with release of histamine. ConclusionsThese experiments show a much shorter neuromuscular blocking effect and much-reduced side effects in the case of GW280430A vis-à-vis mivacurium. These results, together with the novel chemical degradation of GW280430A, suggest further evaluation in human subjects.

Discovery of a Highly Potent, Nonabsorbable Apical Sodium-Dependent Bile Acid Transporter Inhibitor (GSK2330672) for Treatment of Type 2 Diabetes

The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.

Gut Hormone Pharmacology of a Novel GPR119 Agonist (GSK1292263), Metformin, and Sitagliptin in Type 2 Diabetes Mellitus: Results from Two Randomized Studies

GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25–800 mg; n = 45) or multiple doses (100–600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼five-fold compared with placebo, reaching peak concentrations of ∼50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides. Trial Registration: Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621

Short-acting benzodiazepines

council. Education and training are currently among the most important issues in the personal social services. Community care requires social workers to extend their range by adding budgetary, managerial, and coordinating responsibilities to their traditional tasks of assessment and casework. Training must also cover the knowledge and skills required for working with both children and adults and provide the ethical and legal grounding that social work needs. Two years of full time education is too short a time to establish competence across the whole range of a social workers statutory duties; the issue is not whether a third year is desirable but whether it should be spent before or after qualification. Social workers often operate in circumstances where moral values are confused and in conflict and where no single outcome is likely to satisfy all those concerned. Compulsory admission, child care, child protection, fostering and adoption, assessing risk in community and residential careall these are matters on which social workers encounter divided views on values, principles, and policy. Social work must therefore have a secure ethical basis for its professional and educational structures. Practitioners confronted by moral dilemmas and insoluble problems also need the guidance and support of a comprehensive professional organisation. Its advice and findings then form part of the bedrock of professional education. The absence of such a professional structure hampers the incorporation of ethical and technical elements into education. The proposed general council would fill this gap effectively and economically. Social works close association with local government has brought it both costs and benefits. Social workers, in a role that requires professional self-direction, are asked to function as part of the welfare bureaucracy and as front line troops performing statutory duties. But local government also provides social workers with a crucial role in protecting vulnerable people and in securing valuable services for them. It will remain a rewarding setting for the practice of social work, and social workers will continue to make an important contribution to the welfare of the community from a base in local government. The necessary condition is that they receive responsible political leadership, effective management, and proper resources. The narrow focus of statutory services now prevents social work from directly addressing the consequences of unemployment, poverty, and homelessness. A new statutory framework is required for services to adults that redirects the energies of social work to these needs and fulfils all the aspirations of community care policies. Social work should also seek to develop as a professional activity in voluntary and private agencies and in the NHS. The requirement for local authorities to meet the health services need for social work has broken down in significant areas. Health services should once again be able to employ social workers, and social work should be one of the services offered by NHS hospitals and trusts, community health services, and general practices. BILL UTTING Chairman

Synthesis of the putative l-arginine metabolite L-NG-hydroxyarginine

Syntheses of L-NG-hydroxyarginine (1), the putative biosynthetic precursor of nitric oxide, and the 15N labelled analogs 9 and 10 using L-ornithine as the enantiopure starting material is reported.

An efficient and mild synthesis of highly substituted imidazoles

Abstract A versatile, one-step imidazole synthesis employing vicinal tricarbonyl compounds is described.

Identification and structure-activity studies of novel ultrashort-acting benzodiazepine receptor agonists

The synthesis and evaluation of novel ultrashort-acting benzodiazepine (USA BZD) agonists is described. A BZD scaffold was modified by incorporation of amino acids and derivatives. The propionate side chain of glutamic acid tethers an enzymatically labile functionality where the metabolite carboxylic acid displays markedly reduced BZD receptor affinity. The USA BZDs were characterized by full agonism profiles. Copyright2000 Elsevier Science Ltd.

The formation of a covalent complex between a dipeptide ligand and the src SH2 domain.

The X-ray crystal structure of the src SH2 domain revealed the presence of a thiol residue (Cys 188) located proximal to the phosphotyrosine portion of a dipeptide ligand. An aldehyde bearing ligand (1) was designed to position an electrophilic carbonyl group in the vicinity of the thiol. X-ray crystallographic and NMR examination of the complex formed between (1) and the src SH2 domain revealed a hemithioacetal formed by addition of the thiol to the aldehyde group with an additional stabilizing hydrogen bond between the acetal hydroxyl and a backbone carbonyl.

Rapid synthesis of novel dipeptide inhibitors of human collagenase and gelatinase using solid phase chemistry

Abstract Solid phase chemistry expedited the systematic modification of the C and N-terminal groups of cysteine derived lead compound 1 (collagenase IC 50 63nM), providing a series of matrix metalloproteinase inhibitors. Potent inhibitors of collagenase ( 1–2 , 4–6 , and 10–13 ) and gelatinase ( 4–8 ) were identified. Insights into the binding mode of selective inhibitors will be discussed.