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The influence of drug-like concepts on decision-making in medicinal chemistry
TLDR
Analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. Expand
Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor.
TLDR
Results show that dopamine D4 receptor antagonism in the brain does not result in the same neurochemical consequences (increased dopamine metabolism or hyperprolactinemia) observed with typical neuroleptics. Expand
The role of ligand efficiency metrics in drug discovery
TLDR
Optimize ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates. Expand
An analysis of the attrition of drug candidates from four major pharmaceutical companies
TLDR
The compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physic biochemical properties of compounds and clinical failure due to safety issues. Expand
[3H]L-655,708, a Novel Ligand Selective for the Benzodiazepine Site of GABAA Receptors which Contain the α5 Subunit
TLDR
It is concluded that [3H]L-655,708 is the first radioligand to date which is selective for any BZ2 subtype of the GABAA receptor and should provide a valuable tool for elucidating the structure and function of the alpha 5-containing GabAA receptor subtype. Expand
7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex.
TLDR
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. Expand
Is There a Difference between Leads and Drugs? A Historical Perspective
TLDR
Lead structures exhibit, on the average, less molecular complexity, are less hydrophobic, and less druglike (lower druglike scores), and this information should be used in the design of novel combinatorial libraries that are aimed at lead discovery. Expand
Time-related differences in the physical property profiles of oral drugs.
TLDR
Analysis of the 1983-2002 oral drugs by therapy area shows that antiinfectives and nervous system drugs have the most extreme physical property profiles, suggesting that the balance between polar and nonpolar drug properties is an important, unchanging feature of oral drug molecules. Expand
Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is
TLDR
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. Expand
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