A5037689001- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Pharmacogenetics and Drug Metabolism
- Ion channel regulation and function
- Analytical Chemistry and Chromatography
- Tryptophan and brain disorders
- Pharmacological Receptor Mechanisms and Effects
- Neurotransmitter Receptor Influence on Behavior
- Synthesis and Biological Evaluation
- Molecular spectroscopy and chirality
- Amino Acid Enzymes and Metabolism
- Chemical Reactions and Isotopes
- Pharmaceutical Economics and Policy
- Protein Kinase Regulation and GTPase Signaling
- Synthesis and Reactions of Organic Compounds
- Phytase and its Applications
- Phenothiazines and Benzothiazines Synthesis and Activities
- Asymmetric Synthesis and Catalysis
- Analytical Methods in Pharmaceuticals
- Neuroendocrine regulation and behavior
- Fluorine in Organic Chemistry
- Click Chemistry and Applications
- Cancer therapeutics and mechanisms
Nordson (United Kingdom)
2019
GlaxoSmithKline (United Kingdom)
2012-2016
Loughborough University
1999-2011
AstraZeneca (United Kingdom)
1999-2011
MSD (UK) Limited (United Kingdom)
1991-2004
Unilever (Netherlands)
2002
AstraZeneca (Sweden)
2001
Merck & Co., Inc., Rahway, NJ, USA (United States)
1989-1999
University of St Andrews
1995-1997
Molecular Discovery (United Kingdom)
1991
The optimization of low-potency leads into drugs is often accompanied by an increase in molecular weight (M(r)) and lipophilicity, as a consequence affinity enhancement. Hits with at µM levels discovered screening leadlike libraries allow scope for this process, shown schematically the distributions M(r) library (1), oral (2), typical combinatorial chemistry (3). y=percentage particular weight.
To be considered for further development, lead structures should display the following properties: (1) simple chemical features, amenable chemistry optimization; (2) membership to an established SAR series; (3) favorable patent situation; and (4) good absorption, distribution, metabolism, excretion (ADME) properties. There are two distinct categories of leads: those that lack any therapeutic use (i.e., "pure" leads), marketed drugs themselves but have been altered yield novel drugs. We...
The process of drug discovery applies rigorous selection pressures. Marketed oral drugs will generally possess favorable physiochemical properties with respect to absorption, metabolism, distribution, and clearance. This paper describes a study in which the distributions different phases clinical development are compared those already marketed. aim is identify trends that favor drug's successful passage through on market. Two libraries were created, one current marketed drugs. Statistical...
Glycine markedly potentiates N-methyl-D-aspartate (N-Me-D-Asp) responses in mammalian neurons by an action at a modulatory site on the N-Me-D-Asp receptor-ionophore complex. Here we present evidence that 7-chlorokynurenic acid (7-Cl KYNA) inhibits selective antagonism of glycine this site. In rat cortical slices 7-Cl KYNA (10-100 microM) noncompetitively inhibited responses, and effect could be reversed addition (100 or D-serine microM). Radioligand binding experiments showed had much higher...
Comparisons of the calculated physicochemical properties oral drugs launched prior to 1983 (864 drugs) and between 2002 (329 show that mean values lipophilicity, percent polar surface area H-bond donor count are same, suggesting these most important druglike physical properties. In contrast, molecular weight numbers O + N atoms, acceptors, rotatable bonds rings have increased in 1983-2002 (by 13-29%). Analysis by therapy shows antiinfectives nervous system extreme property profiles....
ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXT3-[[4-(4-Chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine: An Antagonist with High Affinity and Selectivity for the Human Dopamine D4 ReceptorJanusz J. Kulagowski, Howard B. Broughton, Neil R. Curtis, Ian M. Mawer, Mark P. Ridgill, Raymond Baker, Frances Emms, Stephen Freedman, Rosemarie Marwood, Shil Patel, Smita C. Ragan, Paul D. LeesonView Author Information Merck Sharp Dohme Research Laboratories, Neuroscience Centre, Terlings Park,...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT4-Amido-2-carboxytetrahydroquinolines. Structure-activity relationships for antagonism at the glycine site of NMDA receptorPaul D. LeesonPaul LeesonMore by Paul Leeson, Robert W. CarlingRobert CarlingMore Carling, Kevin MooreKevin MooreMore Moore, Angela M. MoseleyAngela MoseleyMore Moseley, Julian SmithJulian SmithMore Smith, Graeme StevensonGraeme StevensonMore Stevenson, Tony ChanTony ChanMore Chan, Raymond BakerRaymond BakerMore Baker, Alan C....
The principles of molecular property optimization in drug design have been understood for decades, yet much discovery activity today is conducted at the periphery historical druglike space. Lead trajectories aimed reducing physicochemical risk, assisted by ligand efficiency metrics, could help to reduce clinical attrition rates.
A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett. 2014, 5, 2-5) argued that standard definition ligand efficiency (LE) is mathematically invalid. In this viewpoint, we address criticism and show categorically LE valid. other metrics such as lipophilic (LLE) can be useful during multiparameter optimization challenge faced by medicinal chemists.
Physicochemical descriptors commonly used to define "drug-likeness" and ligand efficiency measures are assessed for their ability differentiate marketed drugs from compounds reported bind efficacious target or targets. Using ChEMBL version 26, a data set of 643 acting on 271 targets was assembled, comprising 1104 drug–target pairs having ≥100 published per target. Taking into account changes in physicochemical properties over time, analyzed according class, therapy area, route...
L-745,870,(3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H- pyrollo[2,3-b] pyridine, was identified as a selective dopamine D4 receptor antagonist with excellent oral bioavailability and brain penetration. L-745,870 displaced specific binding of 0.2 nM [3H] spiperone to cloned human receptors affinity (Ki) 0. 43 which 5- 20-fold higher than that the standard antipsychotics haloperidol clozapine, respectively. exhibited high selectivity for (>2000 fold) compared other subtypes had moderate...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTKynurenic acid derivatives. Structure-activity relationships for excitatory amino antagonism and identification of potent selective antagonists at the glycine site on N-methyl-D-aspartate receptorPaul D. Leeson, Raymond Baker, Robert W. Carling, Neil R. Curtis, Kevin Moore, Brian J. Williams, Alan C. Foster, Angus E. Donald, John A. Kemp, George MarshallCite this: Med. Chem. 1991, 34, 4, 1243–1252Publication Date (Print):April 1, 1991Publication...