M. Jonathan Fray

Pyridyl-phenyl ether monoamine reuptake inhibitors: Impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity.

A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted that potent dual SNRI activity was only achievable at c log P>3.5. The series was found to possess significant polypharmacology issues, and we concluded that this off-target promiscuity was related to lipophilicity.

4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: Design, synthesis and structure–activity relationships

Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.

N-Benzyl-N-(pyrrolidin-3-yl)carboxamides as a new class of selective dual serotonin/noradrenaline reuptake inhibitors.

The structure-activity relationship and the synthesis of novel N-benzyl-N-(pyrrolidin-3-yl)carboxamides as dual serotonin (5-HT) and noradrenaline (NA) monoamine reuptake inhibitors are described. Compounds such as 18 exhibited dual 5-HT and NA reuptake inhibition, good selectivity over dopamine (DA) reuptake inhibition and drug-like physicochemical properties consistent with CNS target space. Compound 18 was selected for further preclinical evaluation.

Application of epimerisation-free amide coupling conditions to the synthesis of matrix metalloprotease inhibitor intermediates

Abstract Coupling of the N-acyltert-leucine derivative 2 with a variety of amines 3a-g gave amides 4a-g in good to excellent yields (75–95%) with minimal epimerisation (≤ 3%) at thetert-leucine stereogenic centre. Limitations of the method are discussed.

Synthesis of 5-Heterocyclic Substituted Quinazolin-4-ones via 2-Aminobenzonitrile Derivatives

Two routes to prepare a series of six 5-heterocyclic substituted 2-chloro-7-methoxyquinazolin-4-ones are described, where the heterocycle is a substituted or unsubstituted 1-pyrazolyl, 5-pyrazolyl or 2-thiazolyl group. Both routes proceeded via key 2-aminobenzonitrile intermediates.

N-[(3S)-Pyrrolidin-3-yl]benzamides as novel dual serotonin and noradrenaline reuptake inhibitors: Impact of small structural modifications on P-gp recognition and CNS penetration

The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.

A Practical Synthesis of 3,3‐Difluorocyclobutane Carboxylic Acid

Abstract We reported a straightforward, three step synthesis of 3,3‐difluorocyclobutane carboxylic acid.

Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: Improving metabolic stability and reducing ion channel activity

New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.

Enantiodifferentiation of dihydropyridine PAF antagonists

Abstract The PAF antagonist activity of a series of enantiomeric dihydropyridines is described. In the first example, 1 , the PAF antagonist activity and calcium channel blocking activity reside in opposite enantiomers. Subsequent examples also display enantioselectivity and the SAR of the series is described.