A5039463029- Synthetic Organic Chemistry Methods
- Marine Sponges and Natural Products
- Chemical synthesis and alkaloids
- Asymmetric Synthesis and Catalysis
- Synthesis and Biological Evaluation
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Estrogen and related hormone effects
- Synthesis and biological activity
- Synthesis and Reactions of Organic Compounds
- Microbial Natural Products and Biosynthesis
- Microwave-Assisted Synthesis and Applications
- Nicotinic Acetylcholine Receptors Study
- Neuropeptides and Animal Physiology
- Alkaloids: synthesis and pharmacology
- Sexual function and dysfunction studies
- Quinazolinone synthesis and applications
- Cholinesterase and Neurodegenerative Diseases
- HER2/EGFR in Cancer Research
- Pharmacological Receptor Mechanisms and Effects
- Chemical Synthesis and Analysis
- Neuroendocrine regulation and behavior
- Medicinal Plants and Neuroprotection
- Ion channel regulation and function
- Traditional and Medicinal Uses of Annonaceae
Pfizer (United Kingdom)
2007-2021
Magee-Womens Hospital
2020
Lothian Sexual Health
2018
Pfizer (United States)
2009-2015
University of Southampton
2008
MSD (UK) Limited (United Kingdom)
2001-2006
University of Cambridge
1996-2005
Merck & Co., Inc., Rahway, NJ, USA (United States)
2002
La Roche College
1971
Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly efficiently. Using traditional paradigms the molecular design, synthesis, screening loops enforce a significant time delay leading inefficient use of data in iterative design process. Here, we report application flow technology platform integrating key elements structure–activity relationship (SAR) generation novel Abl kinase inhibitors. The utilizes chemistry for rapid in-line automated purification,...
The neurotrophin family of growth factors, comprised nerve factor (NGF), brain derived neurotrophic (BDNF), 3 (NT3), and 4 (NT4), is implicated in the physiology chronic pain. Given clinical efficacy anti-NGF monoclonal antibody (mAb) therapies, there significant interest development small molecule modulators activity. Neurotrophins signal through tropomyosin related kinase (Trk) tyrosine receptors, hence Trk inhibition represents a potentially "druggable" point intervention. To deliver...
As an exceptionally potent antimitotic macrolide, altohyrtin A/spongistatin 1 shows great promise in cancer chemotherapy but its extreme scarcity the natural sponges has halted further preclinical development. A highly stereocontrolled total synthesis, which exploits boron-mediated aldol bond constructions, been realized to provide, for first time, a useful amount of synthetic material.
Visceral leishmaniasis is a severe parasitic disease that one of the most neglected tropical diseases. Treatment options are limited, and there an urgent need for new therapeutic agents. Following HTS campaign hit optimization, novel series amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof concept this series.
Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described optimization Nav1.8 modulator series to deliver subtype selective, state, use-dependent chemical matter that is efficacious preclinical models
The design, optimization, and evaluation of a series novel imidazopyridazine-based subtype-selective positive allosteric modulators (PAMs) for the GABAA ligand-gated ion channel are described. From set initial hits multiple subseries were designed evaluated based on binding affinity functional activity. As designing in desired level selectivity proved difficult, probability-based assessment was performed to focus project's efforts single that had greatest odds delivering target profile....
Stereocontrolled syntheses of the C16–C28 CD-spiroacetal subunit altohyrtin A/spongistatin 1 (1), relying on kinetic and thermodynamic control spiroacetal formation, are described. The approach resulted in a slight preference (60 : 40) for desired isomer. allowed ready access to 2 by acid-promoted equilibration, chromatographic separation C23 epimers resubjection undesired isomer equilibration conditions. This scalable synthetic sequence provided multi-gram quantities 2, thus enabling...
An asymmetric total synthesis of (+)-cis-sylvaticin is described. Key steps include the use permanganate-mediated oxidative cyclization 1,5-dienes to synthesize two major fragments 2 and 3 a catalytically efficient tethered RCM unite these THF-containing fragments. In addition, t-BuP4 base was found reliably promote rapid alkylation butenolide precursor fragment 4.
A new synthetic approach to tricyclic pyridones bearing a fused seven-membered ring is described. These compounds exhibit atropisomerism and exist in enantiomeric forms. Chiral HPLC separation of the enantiomers has allowed rates racemization be measured hence free energy barrier for flipping deduced. Introduction further element planar chirality leads diastereomeric atropisomerism. The rate interconversion diastereomers been quantified by 2D EXSY NMR spectroscopy allowing full description...
The recently discovered selective nonsteroidal progesterone receptor (PR) antagonist 4-[3-cyclopropyl-1-(methylsulfonylmethyl)-5-methyl-1<i>H</i>-pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile (PF-02413873) was characterized in metabolism studies vitro, preclinical pharmacokinetics rat and dog, an initial pharmacokinetic study human volunteers. Clearance (CL) of PF-02413873 found to be high (84 ml · min<sup>−1</sup> kg<sup>−1</sup>) low dog (3.8 kg<sup>−1</sup>), consistent with metabolic...
Abstract When subcellular particles from. Rhodopseudophas spheroices wore laced on sucrose density gradients, the separation of chromatophores from cell envelope was markedly affected by presence ionic species. In gradients that contained Tris buffer plus 0.01’ magnesium, were distributed nearly equally between an upper and a lower pigmented band. About half chronatopnores release band when magnesium excluded gradients. exclusion both resulted in quantitative (upper band) (lower ‘and). Thus,...
The hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, is critically important the regulation of blood pressure, but it also several disease, which its actions cancer are becoming recognized to have clinical importance. Reduced circulating causes increased pressure reduces tumor progression, so drugs blocking all effects would be unacceptable clinically. However, there two distinct receptors for adrenomedullin, each comprising same G...
Class B G-protein-coupled receptors (GPCRs) remain an underexploited target for drug development. The calcitonin receptor (CTR) family is particularly challenging, as its are heteromers comprising two distinct components: the receptor-like (CLR) or together with one of three accessory proteins known activity-modifying (RAMPs). CLR/RAMP1 forms a CGRP receptor, CLR/RAMP2 adrenomedullin-1 (AM1) and CLR/RAMP3 adrenomedullin-2 (AM2) receptor. CTR/RAMP complexes form amylin receptors. While...