Paul D Leeson - Academia.edu (original) (raw)

Papers by Paul D Leeson

Nature Reviews Drug Discovery, Jan 31, 2014

 Ligand efficiency measures quantify the molecular properties, particularly size and lipophilici... more  Ligand efficiency measures quantify the molecular properties, particularly size and lipophilicity, of small molecules that are required to gain binding affinity to a drug target. For example, ligand efficiency, is the binding free energy per heavy atom count (LE = G/HA) and lipophilic ligand efficiency (LLE = pIC 50 or Ki-cLogP/D). There are additional efficiency measures for groups in a molecule, and for combinations of size and lipophilicity.  The application of ligand efficiency metrics has been widely reported in the selection and optimisation of fragments, hits, and leads. In particular, optimisation of lipophilic ligand efficiency shows that it is possible to increase affinity and reduce lipophilicity at the same time, even with challenging 'lipophile-preferring' targets.  Mean ligand efficiency measures of molecules acting at a specific target, when combined with their drug-like physical properties, is a practical means of estimating target 'druggability.' This is exemplified with 480 targetassay pairs from the primary literature. Across these targets correlations between biological activity in vitro and physical properties are generally weak, showing that increasing activity by increasing physical properties is not always necessary.  An analysis of 46 recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency and lipophilic ligand efficiencies for their target. Compared with 'only-in-class' oral drugs, on average only 1.5% of all molecules per target possess superior combined ligand efficiency and lipophilic ligand efficiency values.  Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates.

Proceedings of the National Academy of Sciences of the United States of America, Sep 1, 1988

Glycine markedly potentiates N-methyl-Daspartate (N-Me-D-Asp) responses in mammalian neurons by a... more Glycine markedly potentiates N-methyl-Daspartate (N-Me-D-Asp) responses in mammalian neurons by an action at a modulatory site on the N-Me-D-Asp receptorionophore complex. Here we present evidence that 7-chlorokynurenic acid (7-Cl KYNA) inhibits N-Me-D-Asp responses by a selective antagonism of glycine at this modulatory site. In rat cortical slices 7-Cl KYNA (10-100 1AM) noncompetitively inhibited N-Me-n-Asp responses, and this effect could be reversed by the addition of glycine (100 ,AM) or D-serine (100 #M). Radioligand binding experiments showed that 7-Cl KYNA had a much hier affinity for the strychnine-insensitive [3H]glycine binding site (ICse = 0.56 FM) than for the N-Me-D-Asp (ICse 169 pM), quisqualate (ICse = 153 pM), or kainate (IC50 > 1000 pM) recognition sites. In whole-cell patch-clamp recordings from rat cortical neurones in culture, the inhibitory effects of 7-Cl KYNA on N-Me-D-Asp-induced currents could not be overcome by increasing the N-Me-D-Asp concentration but could be reversed by increasing the glycine concentration. 7-Cl KYNA could completely abolish N-Me-D-Asp responses, including basal responses in the absence of added glycine, suggesting that it may possess negative modulatory effects at the glycine site. These findings indicate that the glycine modulatory site is functional in intact adult tissue and that 7-Cl KYNA should prove to be a selective tool for elucidating the involvement of this site in physiological and pathological events mediated by N-Me-D-Asp receptors.

PubMed, May 1, 1992

The glycine site on the N-methyl-D-aspartate (NMDA) subtype of receptors for the excitatory neuro... more The glycine site on the N-methyl-D-aspartate (NMDA) subtype of receptors for the excitatory neurotransmitter glutamate is a potential target for the development of neuroprotective drugs. We report here two chemical series of glycine site antagonists derived from kynurenic acid (KYNA), with greatly improved potency and selectivity. Disubstitution with chlorine or bromine in the 5- and 7-positions of KYNA increased affinity for [3H]glycine binding sites in rat cortex/hippocampus P2 membranes, with a parallel increase of potency for antagonism of NMDA-evoked responses in the rat cortical wedge preparation. The optimal compound was 5-I,7-Cl-KYNA, with an IC50 for [3H]glycine binding of 29 nM and an apparent Kb in the cortical wedge preparation of 0.41 microM. Reduction of the right-hand ring of 5,7-diCl-KYNA reduced affinity by 10-fold, but this was restored by substitution in the 4-position with the trans-phenylamide and further improved in the trans-benzylamide. The optimal compound was the transphenylurea (L-689,560), with an IC50 of 7.4 nM and an apparent Kb of 0.13 microM. Both series of compounds displayed a high degree of selectivity for the glycine site, having IC50 values of greater than 10 microM versus radioligand binding to the glutamate recognition sites of NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate receptors and the strychnine-sensitive glycine receptor. Selectivity versus AMPA receptor-mediated responses was also apparent in the rat cortical wedge and in patch-clamp recordings of cortical neurons in culture. Experiments using [3H]dizocilpine (MK-801) binding indicated that 5,7-diBr-KYNA, 5,7-diCl-KYNA, 5-I,7-Cl-KYNA, and L-689,560 all behaved as full antagonists and were competitive with glycine. Patch-clamp recordings of cortical neurons in culture also indicated that NMDA-induced currents were antagonized by competition for the glycine site, and gave no evidence for partial agonist activity. pKi values for 5,7-diBr-KYNA and L-689,560 in these experiments were 7.2 and 7.98, respectively, similar to the affinities of these compounds in the glycine binding assay. The high affinity and selectivity of these new derivatives make them useful tools to investigate the function of the glycine site on the NMDA receptor.

ACS Infectious Diseases, 2019

In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee... more In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings.

British Journal of Pharmacology, 1994

The anticonvulsant and behavioural effects of the glycine/NMDA receptor partial agonist, L‐687,41... more The anticonvulsant and behavioural effects of the glycine/NMDA receptor partial agonist, L‐687,414 (R(+)‐cis‐β‐methyl‐3‐amino‐1‐hydroxypyrrolid‐2‐one) have been investigated in rodents. L‐687,414 dose‐dependently antagonized seizures induced by N‐methyl‐D, L‐aspartic acid (NMDLA, ED50 = 19.7 mg kg−1), pentylenetetrazol (PTZ, ED50 = 13.0 mg kg−1) and electroshock (ED50 = 26.1 mg kg−1) when given intravenously 15min before test, in male Swiss Webster mice but was most potent against audiogenic seizures induced by a 120 dB bell in DBA/2 mice (ED50 = 5.1 mg kg−1, i.p., 30min before test). L‐687,414 also induced impairments of performance in a rotarod test in both Swiss Webster and DBA/2 mice and the ratio [rotarod MED:anticonvulsant ED50] varied between 0.9 and 5, depending on the convulsant used. Similar behaviours to those seen after administration of the non‐competitive NMDA receptor antagonist, MK‐801 (head weaving, body rolling, hyperlocomotion) were seen in the mouse after giving ...

Proceedings of the National Academy of Sciences, 1990

The antagonist effect of (+/-)-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-asparta... more The antagonist effect of (+/-)-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of (+/-)-HA-966 were resolved, the (R)-(+)-enantiomer was found to be a selective glycine/NMDA receptor antagonist, a property that accounts for its anticonvulsant activity in vivo. In contrast, the (S)-(-)-enantiomer was only weakly active as an NMDA-receptor antagonist, but nevertheless it possessed a marked sedative and muscle relaxant action in vivo. In radioligand binding experiments, (+)-HA-966 inhibited strychnine-insensitive [3H]glycine binding to rat cerebral cortex synaptic membranes with an IC50 of 12.5 microM, whereas (-)-HA-966 had an IC50 value of 339 microM. In electrophysiological experiments, (+)-HA-966 selectively antagonized NMDA receptor responses in rat cortical slices, whereas the (-)-enantiomer was much weaker. On cultured cor...

Biochemical Journal, 1988

1. Hydrolysis of both enantiomers of inositol 1-phosphate and both enantiomers of inositol 4-phos... more 1. Hydrolysis of both enantiomers of inositol 1-phosphate and both enantiomers of inositol 4-phosphate to inositol is inhibited by LiCl in liver and brain. 2. The phosphatase activity is predominantly soluble. 3. Inositol 1,4-bisphosphate is also hydrolysed by the soluble fraction of liver and brain. 4. Bisphosphatase activity is inhibited by LiCl, but is less sensitive than monophosphatase activity. 5. The product of bisphosphatase in liver and brain is inositol 4-phosphate.

A compilation of attrition data for oral development compounds nominated by four large pharmaceut... more A compilation of attrition data for oral development compounds nominated by four large pharmaceutical companies (AstraZeneca, Eli Lilly, GlaxoSmithkline and Pfizer) in the period 2000 to 2010 has been carried out. It was anticipated that pooling data would help to minimize any issues of inter-company variability as described above and that the larger dataset would increase the chances of observing meaningful relationships. Here, the nature of this compiled dataset and an analysis of the causes of attrition, with a focus on toxicology and safety, are described. The links between these observations and the physical properties of the drug candidates are assessed

Molecular pharmacology, 1992

Bioorganic & Medicinal Chemistry Letters, 2007

Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y 12 recept... more Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y 12 receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.

J. Chem. Soc., Perkin …, 1988

The key step in the synthesis of -3,5-dibromo-3′-[6-oxo-1,6-dihydropyridazin-3-yl)methyl]- thyron... more The key step in the synthesis of -3,5-dibromo-3′-[6-oxo-1,6-dihydropyridazin-3-yl)methyl]- thyronine, SK&F L-94901 (), a novel, selective, and potent thyromimetic, is the formation of the hindered diaryl ether moiety. This paper describes an investigation into the formation of the ...

J Chem Soc Perkin Trans 1, 1995

To be considered for further development, lead structures should display the following properties... more To be considered for further development, lead structures should display the following properties: (1) simple chemical features, amenable for chemistry optimization; (2) membership to an established SAR series; (3) favorable patent situation; and (4) good absorption, distribution, metabolism, and excretion (ADME) properties. There are two distinct categories of leads: those that lack any therapeutic use (i.e., "pure" leads), and those that are marketed drugs themselves but have been altered to yield novel drugs. We have previously analyzed the design of leadlike combinatorial libraries starting from 18 lead and drug pairs of structures (S. J. Teague et al. Angew. Chem., Int. Ed. Engl. 1999, 38, 3743-3748). Here, we report results based on an extended dataset of 96 lead-drug pairs, of which 62 are lead structures that are not marketed as drugs, and 75 are drugs that are not presumably used as leads. We examined the following properties: MW (molecular weight), CMR (the calculated molecular refractivity), RNG (the number of rings), RTB (the number of rotatable bonds), the number of hydrogen bond donors (HDO) and acceptors (HAC), the calculated logarithm of the n-octanol/water partition (CLogP), the calculated logarithm of the distribution coefficient at pH 7.4 (LogD 74 ), the Daylight-fingerprint druglike score (DFPS), and the property and pharmacophore features score (PPFS). The following differences were observed between the medians of drugs and leads: ∆MW ) 69; ∆CMR ) 1.8; ∆RNG ) ∆HAC )1; ∆RTB ) 2; ∆CLogP ) 0.43; ∆LogD 74 ) 0.97; ∆HDO ) 0; ∆DFPS ) 0.15; ∆PPFS ) 0.12. Lead structures exhibit, on the average, less molecular complexity (less MW, less number of rings and rotatable bonds), are less hydrophobic (lower CLogP and LogD 74 ), and less druglike (lower druglike scores). These findings indicate that the process of optimizing a lead into a drug results in more complex structures. This information should be used in the design of novel combinatorial libraries that are aimed at lead discovery.

Journal of the Chemical Society Chemical Communications, 1989

... Brian J. Williams, Paul D. Leeson, Graeme Hannah, and Raymond Baker Merck Sharp and Dohme Res... more ... Brian J. Williams, Paul D. Leeson, Graeme Hannah, and Raymond Baker Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road ... 14 R. D. Cooper, F. Jose, L. McShane, and KA Koppel, Tetrahedron Lett., 1978, 19, 2243. ...