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John Saunders

Publications and source records attributed to John Saunders.

At least 55 records · Page 3Linked to original sources
PubMed2003

Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidine-2,4-dione derivatives as potent GnRH receptor antagonists.

The synthesis and SAR studies of thieno[2,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists to treat reproductive diseases are discussed. It was found that the 2-(2-pyridyl)ethyl group on the 5-aminomethyl functionality of the core structure was a key feature for good receptor binding activity. SAR study of the 6-(4-aminophenyl) group suggests that hydrophobic substituents were preferred. The best compound from this series had binding affinity (K(i)) of 0.4 nM to the human GnRH receptor.

Pyrimidinones↗
PubMed2003

Synthesis and structure-activity relationships of 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils as antagonists of the human GnRH Receptor.

A new class of small molecule GnRH antagonists, the 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils, was designed and a novel stereoselective synthesis for these compounds was developed. The stereochemical integrities of key intermediates (S)-6 and (R)-6 were confirmed by a combination of X-ray crystallography and chiral HPLC determinations. SAR studies were performed, which allowed the identification of derivatives (R)-9f, (R)-9h and (R)-12 as potent hGnRH antagonists (K(i)=20 nM).

Dose-Response Relationship, Drug↗
PubMed2003

Synthesis and structure-activity relationships of 1-arylmethyl-3-(2-aminopropyl)-5-aryl-6-methyluracils as potent GnRH receptor antagonists.

The novel synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed. Introduction of a small methyl substituent at the beta-position from N3 of the uracil improved the GnRH binding potency by 5- to 10-fold. The best compound from the series had binding affinity of 5 nM (K(i)) to the human GnRH receptor.

Dose-Response Relationship, Drug↗
PubMed2003

Identification of 1-arylmethyl-3- (2-aminoethyl)-5-aryluracil as novel gonadotropin-releasing hormone receptor antagonists.

Based on SAR from bicyclic GnRH antagonists such as 6-aminomethyl-7-arylpyrrolo[1,2-a]pyrimid-4-ones (1) and 2-aryl-3-aminomethylimidazolo[1,2-a]pyrimid-5-ones (2a,b), a series of novel uracil compounds (4) were derived as the GnRH antagonists. Their syntheses and initial SAR are discussed herein. This is the first time that monocycle-based GnRH receptor antagonists are reported.

Animals↗
PubMed2003

Design and structure-activity relationships of 2-alkyl-3-aminomethyl-6-(3-methoxyphenyl)-7-methyl-8-(2-fluorobenzyl)imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists.

SAR studies of 7-phenylpyrrolo[1,2-a]pyrimid-4-ones 1 and 2, and 2-phenylimidazolo[1,2-a]pyrimidines 3 and 4, as nonpeptide human GnRH receptor antagonists, lead us to believe that the aromatic ring at position-2 of 4 is no longer crucial for the binding once an aryl group is incorporated at postion-6. We report here the use of a 2-alkyl group on the imidazolo[1,2-a]pyrimidone core to generate potent GnRH receptor antagonists. This discovery enabled us to obtain smaller but equally potent GnRH receptor antagonists.

Drug Design↗
PubMed2003

Body weight regulation by selective MC4 receptor agonists and antagonists.

There has been great interest in melanocortin (MC) receptors as targets for the design of novel therapeutics to treat disorders of body weight, such as obesity and cachexia. Both genetic and pharmacological evidence points toward central MC4 receptors as the principal target. Using highly selective peptide tools for the MC4 receptor, which have become available recently, we have provided pharmacological confirmation that central MC4 receptors are the prime mediators of the anorexic and orexigenic effects reported for melanocortin agonists and antagonists, respectively. The current progress with receptor-selective small molecule agonist and antagonist drugs should enable the therapeutic potential of MC4 receptor activation and inhibition to be assessed in the clinic in the near future.

Animals↗
PubMed2003

The melanocortin system and its role in obesity and cachexia.

Melanocortin receptors (MC-R) activated by one of several peptides derived from the pro-opiomelanocortin (POMC) precursor have become leading contenders for a pivotal role in controlling food intake. Evidence has emerged over the last decade to implicate primarily the MC4-R and, to a lesser extent, MC3-R as the key sub-types involved and both are strategically located in those regions within the hypothalamus known to be associated with feeding. The receptors are within class A of the GPCR superfamily and the key electrostatic interaction with the positively charged peptide (Arg) has been mapped to one or more Asp or Glu residues located on helices II and III of the seven helical bundle characteristic of this class of receptor. Sites for secondary interactions from which sub-type selectivity may be derived have also been located in the extracellular and helical domains. Unique amongst GPCRs is the presence of endogenous antagonist peptides, Agouti and Agouti-related peptide (AGRP), which confer an extra level of control on the system. Recently, several reports of potent and selective non-peptide ligands have been published and these are seen as prototypic molecules from which drugs may emerge to treat obesity (agonists) and cachexia (antagonists). The role played by the melanocortin system is the subject of this review and advances in our understanding of the structure of the endogenous ligand(s), non-peptide, small molecule ligands and the receptors at which they interact will be discussed.

Amino Acid Sequence↗
PubMed2002

A novel synthesis of 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones as potent, stable GnRH receptor antagonists.

A new class of small molecule GnRH antagonists, the 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones, was designed and a novel synthesis for these compounds was developed. The synthesis utilizes a base-catalyzed intramolecular cyclization of fluoromethyl pyrimidone 5 to generate the bicyclic core. Amongst the compounds synthesized, we discovered some highly potent GnRH receptor antagonists (e.g., 12, K(i)=9 nM), which showed enhanced stability towards acidic physiological conditions compared to the des-fluoro analogues.

Calcium↗
PubMed2002

Synthesis and initial structure-activity relationships of a novel series of imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists.

SAR studies of 2-arylimidazolo[1,2-a]pyrimid-5-ones 10a-m, which were derived from initial lead 3a, resulted in the discovery of a series of potent nonpeptide human GnRH receptor antagonists. Compounds with good potency (e.g., 10e, K(i)=7.5 nM) were prepared by introduction of a 2-(2-pyridyl)ethyl at the basic nitrogen and a 3-pentyl ester at the 6-position of the bicyclic core.

Binding Sites↗
PubMed2002

Design, synthesis and structure-activity relationships of novel imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists.

SAR studies of lead GnRH receptor antagonists 2a and 2b reported earlier resulted in the discovery of compound 10b which showed much higher potency (K(i)=4.6 nM, compared with 2b, K(i)=230 nM) in which the 7-position of the imidazolo[1,2-a]pyrimidone core was substituted with a methyl group, and the ester at the 6-position was replaced by the 3-methoxyphenyl group.

Animals↗
PubMed2002

A novel synthesis of 2-arylpyrrolo[1,2-a]pyrimid-7-ones and their structure-activity relationships as potent GnRH receptor antagonists.

In the process of developing GnRH receptor antagonists, a novel base-catalyzed cyclization of compounds 5a-b was discovered, which led to the formation of the 2-aryl pyrrolo[1,2-a]pyrimid-7-one core structures 6a-b. These intermediates were further modified at positions 1, 2, 4 and 6 to afford a series of potent GnRH antagonists with low nanomolar K(i) values.

Animals↗
PubMedDate not supplied

Attitudes and management of alcohol problems in general practice: descriptive analysis based on findings of a World Health Organization international collaborative survey.

AIMS: To determine if general practitioners' (GPs) experience of education on alcohol, support in their working environment for intervening with alcohol problems, and their attitudes have an impact on the number of patients they manage with alcohol problems. METHODS: 1300 GPs from nine countries were surveyed with a postal questionnaire as part of a World Health Organization (WHO) collaborative study. RESULTS: GPs who received more education on alcohol (OR = 1.5; 95% CI, 1.3-1.7), who perceived that they were working in a supportive environment (OR = 1.6; 95% CI, 1.4-1.9), who expressed higher role security in working with alcohol problems (OR = 2.0; 95% CI, 1.5-2.5) and who reported greater therapeutic commitment to working with alcohol problems (OR = 1.4; 95% CI, 1.1-1.7) were more likely to manage patients with alcohol-related harm. CONCLUSION: Both education and support in the working environment need to be provided to enhance the involvement of GPs in the management of alcohol problems.

Alcohol-Related Disorders↗
PubMedDate not supplied

Challenges to medications development in treating alcohol dependence: an international perspective.

Few medications for treating alcohol dependence exist. Greater partnership is needed between academia and the pharmaceutical industry to develop, licence and market efficacious medications for treating alcohol dependence. Methodologies that span the divide between preclinical and large-scale clinical studies need to be developed in order to provide sufficient information on safety, toleration, drug-interaction profile and efficacy, with which to guide development decisions. Due to the heterogeneous nature of alcohol dependence, the effort of developing an efficacious medication is likely to be enhanced by clearer choices about the characteristics of the population. Careful consideration of potential mechanism of action of the putative therapeutic medication should enable the appropriate choice of drinking endpoint. The pharmaceutical industry in collaboration with academia might need to develop new approaches to determining appropriate treatment endpoints with regulatory bodies. The investment risk to industry should be appraised not only in terms of the rather poor results of previous marketing efforts but with a view to the opportunity to penetrate a potentially enormous and largely untapped market.

Alcoholism↗
PubMedDate not supplied

Research ethics committees--time for change?

Research ethics committees have developed over the last 30 years in the UK. As their roles and responsibilities have grown, so too has the complexity of their work. This poses increasing problems which cannot be solved within the current structure. This article suggests that the present large number of volunteer committees be replaced by a much smaller number of fully professional bodies in order to increase speed, efficiency and consistency of working.

Ethical Review↗