William Potts
AstraZeneca
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Featured researches published by William Potts.
NeuroImage | 2008
M. Edward Pierson; Jan Andersson; Svante Nyberg; Dennis J. McCarthy; Sjoerd J. Finnema; Katarina Varnäs; Akihiro Takano; Per Karlsson; Balázs Gulyás; Amy Medd; Chi-Ming Lee; Mark E. Powell; J. Richard Heys; William Potts; Nicholas Seneca; Ladislav Mrzljak; Lars Farde; Christer Halldin
The 5-HT1B receptor has been implicated in several psychiatric disorders and is a potential pharmacological target in the treatment of depression. Here we report the synthesis of a novel PET radioligand, [11C]AZ10419369 (5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide), for in vivo visualization of 5-HT1B receptors in the brains of macaques and humans subjects. [11C]AZ10419369 was prepared by N-methylation of (8-(1-piperazinyl)-5-methylchrom-2-en-4-one-2-(4-morpholinophenyl) carboxamide, using carbon-11 methyl triflate. Regional brain uptake patterns of [11C]AZ10419369 were characterized by PET measurements in two macaques and a preliminary study in two human subjects. In addition, AZ10419369 was prepared in tritium labeled form for in vitro autoradiography studies in macaque brain tissue sections. The radiochemical purity of [11C]AZ10419369 was >99% and specific radioactivity was >3600 Ci/mmol. After iv injection of [11C]AZ10419369, 3-4% was in brain after 7.5 min. The regional brain distribution of radioactivity was similar in humans and macaques showing the highest uptake of radioactivity in the occipital cortex and the basal ganglia, in accord with autoradiographic studies performed using [3H]AZ10419369. Uptake was moderate in the temporal and frontal cortical regions, lower in the thalamus and lowest in the cerebellum. In macaques pre-treated with the selective 5-HT1B receptor antagonist, AR-A000002, binding was reduced in a dose-dependent manner, consistent with specific binding to 5-HT1B receptors. These data support [11C]AZ10419369 as a suitable radioligand for labeling 5-HT1B receptors in the primate brain. This radioligand may be useful in future studies evaluating drug-induced receptor occupancy and measurement of brain 5-HT1B receptor levels in patients with psychiatric disorders.
Bioorganic & Medicinal Chemistry Letters | 2001
Peter Bernstein; David Aharony; Jeffrey S. Albert; Donald W. Andisik; Herbert Barthlow; Russell Bialecki; Timothy Wayne Davenport; Robert F. Dedinas; Bruce T. Dembofsky; Gerard M. Koether; Benedict J. Kosmider; Karin Kirkland; Cyrus John Ohnmacht; William Potts; William L. Rumsey; Lihong Shen; Ashok Shenvi; Scott Sherwood; David Stollman; Keith Russell
Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (K(i)=0.12 and 0.62nM, respectively). In functional assays ZD6021 had, at 10(-7)M, in human pulmonary artery pK(B)=8.9 and in human bronchus pK(B)=7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED(50)=0.5mg/kg, and NK2 mediated bronchoconstriction, ED(50)=13mg/kg.
Journal of Medicinal Chemistry | 2014
Dean G. Brown; Peter R. Bernstein; Andrew Griffin; Steve Wesolowski; Denis Labrecque; Maxime C. Tremblay; Mark Sylvester; Russell C. Mauger; Phillip D. Edwards; Scott Throner; James Folmer; Joseph Cacciola; Clay W Scott; Lois Ann Lazor; Mehrnaz Pourashraf; V. Santhakumar; William Potts; Simon Sydserff; Pascall Giguère; Carine Lévesque; Mohammed Dasser; Thierry Groblewski
A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.
Expert Opinion on Therapeutic Patents | 2006
Jeffrey S. Albert; William Potts
Two neurokinin-3 receptor (NK3r) antagonists, osanetant and talnetant, have recently shown positive results in clinical trials for schizophrenia. Following these disclosures, research has accelerated significantly. This review focuses on progress for NK3r antagonists since 2004, primarily from the patent literature. The emphasis here is on NK3r antagonists as treatments for schizophrenia. In addition, antagonists of NK3r that have efficacy at NK1r and/or NK2r have also been explored as antipsychotics or as treatments for other psychiatric disorders and these will be included in this review.
Bioorganic & Medicinal Chemistry Letters | 2010
Jeffrey G. Varnes; Janet Marie Forst; Tiffany N. Hoerter; Christopher R. Holmquist; Deidre E. Wilkins; Gaochao Tian; Gerald Jonak; Xia Wang; William Potts; Michael W. Wood; Cristobal Alhambra; Todd Andrew Brugel; Jeffrey S. Albert
A novel series of glycine transporter 1 (GlyT1) inhibitors is described. Scoping of the heterocycle moiety of hit 4-chlorobenzenesulfonamide 1 led to replacement of the piperidine with an azepane for a modest increase in potency. Phenyl sulfonamides proved superior to alkyl and non-phenyl aromatic sulfonamides, while subsequent ortho substitution of the 2-(azepan-1-yl)-2-phenylethanamine aromatic ring yielded 39 (IC(50) 37 nM, solubility 14 microM), the most potent GlyT1 inhibitor in this series. Favorable brain-plasma ratios were observed for select compounds in pharmacokinetic studies to evaluate CNS penetration.
Bioorganic & Medicinal Chemistry Letters | 2018
Jeffrey G. Varnes; Hui Xiong; Janet Marie Forst; Christopher R. Holmquist; Glen Ernst; William Frietze; Bruce T. Dembofsky; Don Andisik; William E. Palmer; Lindsay Hinkley; Gary Steelman; Deidre E. Wilkins; Gaochao Tian; Gerald Jonak; William Potts; Xia Wang; Todd Andrew Brugel; Cristobal Alhambra; Michael W. Wood; Chris Allan Veale; Jeffrey S. Albert
A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 μmol/kg compared to control.
Journal of Medicinal Chemistry | 2002
Jeffrey S. Albert; David Aharony; Donald W. Andisik; Herbert Barthlow; Peter R. Bernstein; Russell Bialecki; Robert F. Dedinas; Bruce T. Dembofsky; Daniel Hill; Karin Kirkland; Gerard M. Koether; Benedict J. Kosmider; Cyrus John Ohnmacht; William E. Palmer; William Potts; W. L. Rumsey; Lihong Shen; Ashok B. Shenvi; Scott Sherwood; Paul James Warwick; Keith Russell
Tetrahedron | 2004
Jeffrey S. Albert; Cyrus John Ohnmacht; Peter Bernstein; William L. Rumsey; David Aharony; Brian B. Masek; Bruce T. Dembofsky; Gerard M. Koether; William Potts; John Evenden
Journal of Medicinal Chemistry | 2004
Jeffrey S. Albert; Cyrus J. Ohnmacht; Peter R. Bernstein; W. L. Rumsey; David Aharony; Yun Alelyunas; Daniel J. Russell; William Potts; Scott Sherwood; Lihong Shen; Robert F. Dedinas; William E. Palmer; Keith Russell
Archive | 2007
John Richard Heys; Edward Pierson; William Potts