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Biomedical subjects

John Saunders

Publications and source records attributed to John Saunders.

At least 19 recordsLinked to original sources
PubMed2005

Synthesis and structure-activity relationships of biarylcarboxamide bis-aminopyrrolidine urea derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1).

A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.

Amides↗
PubMed2005

Potent, orally active corticotropin-releasing factor receptor-1 antagonists containing a tricyclic pyrrolopyridine or pyrazolopyridine core.

Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC(50) = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V(D) = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.

Acenaphthenes↗
PubMed2005

A potent and selective nonpeptide antagonist of the melanocortin-4 receptor induces food intake in satiated mice.

Optimization on a series of piperazinebenzylamines resulted in analogues with low nanomolar binding at the human MC4 receptor but weak affinity (Ki > 500 nM) at the MC3 receptor. Compound 14c was identified to be a potent MC4R antagonist (Ki = 3.2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration.

Animals↗
PubMed2005

Rational design, synthesis, and structure-activity relationships of aryltriazoles as novel corticotropin-releasing factor-1 receptor antagonists.

Following the discovery of the very high binding affinity of 4-anilinopyrimidines against corticotropin-releasing factor receptor-1 (CRF(1)) (e.g., 1, K(i) = 2 nM), a new series of triazoles bearing different groups has been synthesized and evaluated. The compounds were prepared by cyclizations of N-acyl-S-methylisothioureas with alkylhydrazines or by cyclizations with hydrazine followed by alkylation. While members of this series showed potent binding affinity against CRF(1) receptor, there were important differences between the different regio- (7 and 12) and stereoisomeric aryltriazoles where the R(1) or R(2) side chain in 7 has an asymmetric center. In terms of overall potency, aryltriazole analogues such as 7r bearing an N-(alpha-branched benzyl)-N-propylamino side chain were the most potent, followed by analogues such as 7a, with an N-bis(cyclopropyl)methyl-N-propylamino side chain, and analogues such as 7m, with an N-(alpha-branched aliphatic)-N-propylamino side chain. While the N-propyl group was crucial for high potency, we hypothesized that the terminal methyl mimicked the 5-methyl of pyrazolo[1,5-a]pyrimidines 3 and 4. Correlation of the low-energy conformers of compounds of type 3 and 7 generated by computational analyses was very good. The size and shape of the N-alkyl group dramatically changed the potency of the triazoles, which is in contrast to the SAR seen for bicyclic CRF(1) antagonists. In general, the S-enantiomer was much more potent than the corresponding R-isomer. Furthermore, to a limited extent in the aryltriazole series the substituent on the 5-phenyl ring changed the potency up to 9-fold. (S)-1-Methyl-3-[N-(4-fluorophenylpentyl)-N-propyl]amino-5-(2-methoxy-4-dichlorophenyl)-1H-[1,2,4]triazole [(S)-7r] showed very potent binding affinity (K(i) = 2.7 nM) to CRF(1) receptors with an IC(50) of 49 nM in a cAMP inhibition assay.

Animals↗
PubMed2005

3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization.

Further structure-activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (R-13b, NBI 42902) displayed subnanomolar binding affinity (K(i) = 0.56 nM) and was a potent functional antagonist (IC(50) = 3.0 nM in Ca(2+) flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (K(i) = 3.9 nM). In addition, R-13bhad good plasma exposure in cynomolgus monkeys after oral administration, with a C(max) of 737 ng/mL and an AUC of 2392 ng/mL.h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.

Administration, Oral↗
PubMed2005

Bis(aminopyrrolidine)-derived ureas (APUs) as potent MCH1 receptor antagonists.

Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).

Dose-Response Relationship, Drug↗
PubMed2005

Identification of agonists and antagonists of the human melanocortin-4 receptor from piperazinebenzylamines.

SAR studies of a series of piperazinebenzylamines resulted in identification of potent agonists and antagonists of the human melanocortin-4 receptor. Thus, the 1,2,3,4-tetrahydroisoquinolin-1-ylacetyl compound 12e and the quinolin-3-ylcarbonyl analogue 12l possessed K(i) values of 6.3 and 4.5 nM, respectively. Interestingly, 12e was a full agonist with an EC(50) value of 31 nM, and 12l was a weak partial agonist (IA=17%) and functioned as an antagonist (IC(50)=300 nM).

Benzylamines↗
PubMed2005

A convenient one-pot synthesis of asymmetric 1,3,5-triazine-2,4,6-triones and its application towards a novel class of gonadotropin-releasing hormone receptor antagonists.

A convenient one-pot synthetic route was developed for the preparation of asymmetric 1,3-dialkyl-1,3,5-triazine-2,4,6-triones from readily available alkyl- or aryl-isocyanates, primary amines and N-chlorocarbonyl isocyanate in excellent yields. Subsequent alkylation with N-protected amino alcohols afforded the desired 1,3,5-triazine-2,4,6-triones in good yields. This methodology was applied to the synthesis of a chemical library acting as antagonists of the hGnRH receptor.

Alkylation↗
PubMed2005

A multicountry controlled trial of strategies to promote dissemination and implementation of brief alcohol intervention in primary health care: findings of a World Health Organization collaborative study.

OBJECTIVE: This study examines the impact of marketing strategies on the dissemination of a brief alcohol intervention program to general practitioners (GPs). The marketing strategy was tested to determine the most effective way to promote awareness about and consideration of a brief alcohol intervention program. The study also examines the impact of training and support strategies to promote the program's implementation in routine primary care. METHOD: A pragmatic trial was carried out in Australia, Belgium (Flanders), Denmark, England, New Zealand and Spain (Catalonia) in which GPs were randomly allocated into one of three marketing conditions (direct mail, telemarketing and academic detailing [personal visits]). The GPs who requested a brief intervention program and agreed to use it were stratified by previous marketing condition and randomly allocated into one of three implementation strategy groups: written guidance, outreach training and outreach training plus ongoing telephone support. RESULTS: Acceptance of the brief intervention program was more effective with use of telemarketing (65%) and academic detailing (67%) than with direct mail (32%) for promoting awareness about and consideration of a brief alcohol intervention program. The median proportion of patients screened was higher for trained GPs (6%) and supported GPs (9%) than for control GPs (1%), who received only written guidance on how to conduct brief intervention. Similarly, the median rate for giving advice to at-risk patients was higher for trained GPs (3%) and supported GPs (3%) than for control GPs (0%). CONCLUSIONS: The adoption of more direct approaches for disseminating evidence-based intervention programs to GPs is a necessary first step for changing practice behavior. However, outreach training was required to promote actual use of a new procedure in routine practice.

Adult↗
PubMed2004

A screening library for peptide activated G-protein coupled receptors. 1. The test set.

One subset of the G-protein coupled receptor (GPCR) superfamily is that which is activated by a peptide carrying an obligatory positively charged residue (GPCR-PA(+)). This subclass is exemplified by receptors for melanocortins, GnRH, galanin, MCH, orexin, and some chemokine receptors variously involved in eating disorders, reproductive disorders, pain, narcolepsy, obesity, and inflammation. Using the methods described in this study, a region of chemical property space enriched in GPCR ligands was identified. This information was used to design and synthesize a "test" library of 2025 single, pure compounds to sample portions of this property space associated with GPCR-PA(+) ligands. The library was evaluated by high-throughput screening against three different receptors, rMCH, hMC4, and hGnRH, and found to be highly enriched in active ligands (4.5-61-fold) compared to a control set of 2024 randomly selected compounds. In addition, the analysis suggested that about 7000 compounds will be necessary to complete the sampling of this GPCR-PA(+) ligand-rich region and to better define its borders.

Animals↗
PubMed2004

4-{(2R)-[3-Aminopropionylamido]-3-(2,4-dichlorophenyl)propionyl}-1-{2-[(2-thienyl)ethylaminomethyl]phenyl}piperazine as a potent and selective melanocortin-4 receptor antagonist--design, synthesis, and characterization.

Recent studies have demonstrated that melanocortin-4 receptor (MC4R) antagonists can prevent weight loss in tumor-bearing mice, which indicates clinical usage for the treatment of cachexia. In our efforts to develop potent and selective antagonists of the human MC4R, we designed piperazinebenzylamines bearing a 2,4-dichlorophenylalanine, by utilizing information derived from structure--activity relationships of MC4R agonists and mutagenesis results of the MC4R and peptide ligands. On the basis of known MC4R agonists such 6, we successfully synthesized potent MC4R antagonists exemplified by 10, which possesses a K(i) value of 1.8 nM in binding affinity. 10 does not stimulate cAMP release in HEK 293 cells expressing the human MC4 receptor at 10 microM concentration. It was demonstrated by Schild analysis that 10 was a competitive functional antagonist with a pA(2) value of 7.9 in the inhibition of alpha-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats.

Animals↗
PubMed2004

Piperazinebenzylamines as potent and selective antagonists of the human melanocortin-4 receptor.

SAR studies of a series of piperazinebenzylamines resulted in the discovery of potent antagonists of the human melanocortin-4 receptor. Compounds 11c, 11d, and 11l, which had K(i) values of 21, 14, and 15 nM, respectively, possessed low efficacy in cAMP stimulation ( approximately 15% of alpha-MSH maximal level) mediated by MC4R, and functioned as antagonists in inhibition of alpha-MSH-stimulated cAMP release in a dose-dependent manner (11l, IC(50)=36 nM).

Benzylamines↗
PubMed2004

Small molecule inhibitors of the CCR2b receptor. Part 1: Discovery and optimization of homopiperazine derivatives.

N,N'-Disubstituted homopiperazine derivatives have been discovered as CC-chemokine receptor 2b (CCR2b) inhibitors with submicromolar activity in the CCR2b binding assay. A 4-substituted benzyl group on one homopiperazine nitrogen was an important moiety for binding affinity to the CCR2b receptor. The SAR for CCR2b binding affinity correlated inversely with the sigma factor of the functional group on this benzyl moiety. Introduction of hydroxy groups to appropriate positions in the 3,3-diphenylpropyl group on the other homopiperazine nitrogen increased CCR2b binding activity. The synthesis of an informer library to search for alternative substructures is also described.

Cell Line↗
PubMed2004

Synthesis and structure-activity relationships of uracil derived human GnRH receptor antagonists: (R)-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5.

The synthesis of a series of (R)-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5 is described. SAR around C-5 of the uracil led to the discovery that a 2-thienyl or (2-phenyl)thiazol-4-yl group is required for optimal receptor binding. The best compound from the series had a binding affinity of 2 nM (K(i)) for the human GnRH receptor. A novel and convenient preparation of N-1-(2,6-difluorobenzyl)-6-methyluracil is also described.

Humans↗
PubMed2004

Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure--activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists.

We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF(1) receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26 h exhibited good binding affinity at the human CRF(1) receptor with a K(i) value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF(1) receptor (IC(50) = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC(50) = 20 nM). 26 h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26 h was orally bioavailable and able to penetrate into the brain. 26 h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF(1) receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26 h was developed into a clinical compound and exhibited efficacy in patients with major depression.

Adrenocorticotropic Hormone↗