Per Olaf Huusfeldt
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Featured researches published by Per Olaf Huusfeldt.
Bioorganic & Medicinal Chemistry | 2001
Knud Erik Andersen; Jesper Lau; Behrend F. Lundt; Hans Petersen; Per Olaf Huusfeldt; Peter D. Suzdak; Michael D. B. Swedberg
In a previous series of potent GABA uptake inhibitors published from this laboratory, we noticed that asymmetry in the substitution pattern of the bis-aromatic moiety in known GABA uptake inhibitors such as 4 [1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid] and 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid] was beneficial for high affinity. This led us to investigate asymmetric analogues of known symmetric GABA uptake inhibitors in which one of the aryl groups has been exchanged with an alkyl, alkylene or cycloalkylene moiety as well as other modifications in the lipophilic part. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound, and it was found that several of the novel compounds inhibit GABA uptake as potently as their known symmetrical reference analogues. Several of the novel compounds were also evaluated for their ability to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in vivo. Some of the compounds, for example 18 [(R)-1-(2-(((1,2-bis(2-fluorophenyl)ethylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid], show a high in vivo potency and protective index comparable with that of our recently launched anticonvulsant product, 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid], and may therefore serve as second-generation drug candidates.
Bioorganic & Medicinal Chemistry | 2003
Martin Wenckens; Palle Jakobsen; Per Vedsø; Per Olaf Huusfeldt; Birgitte Gissel; Marianne Barfoed; Bettina Lundin Brockdorff; Anne E. Lykkesfeldt; Mikael Begtrup
The preparation of a series of novel analogues of the selective antiestrogen tamoxifen is reported. 1Z-alkoxyphenyl group in tamoxifen has been replaced by a N-alkoxypyrazole, while functionalised phenyl groups or heteroaromatics were introduced at the 2Z-position using sequential Suzuki cross coupling of 1,2-(bis)borylpinacol 1-phenylbutene with 4- or 5-iodo-1-N,N-dimethylaminoethyl or propyl-pyrazoles. Approximately 50 tamoxifen analogues were obtained and tested in an estrogen receptor (ERalpha) affinity assay. Several compounds exhibited binding affinities 2-5-fold lower than tamoxifen. Dose-response experiments with six selected compounds were carried out using two different human breast cancer cell lines, MCF-7 and the tamoxifen resistant cell line MCF-/TAM(R)-1. Both cell lines exhibited growth inhibition upon treatment with the tamoxifen analogues. Co-treatment of the cells, with estradiol and the individual compounds, were also performed. The results indicated that the observed growth inhibitory effect was mediated by the ERalpha. Analogues of the potent antiestrogen 4-hydroxytamoxifen (4-OHT) were synthesised where the 1E-4-hydroxyphenyl was replaced by a 1-hydroxypyrazol-4-yl group. However, modest growth inhibition of MCF-7 cells was observed upon treatment with these analogues. In contrast, 1Z-, 2Z-ringclosed tamoxifen analogue (59) was shown to possess antiproliferative effects on MCF-7 and MCF-/TAM(R)-1 cells in lower doses than tamoxifen.
Journal of The Chemical Society-perkin Transactions 1 | 2001
Jan Pawlas; Jeremy R. Greenwood; Per Vedsø; Tommy Liljefors; Palle Jakobsen; Per Olaf Huusfeldt; Mikael Begtrup
Selective C* halogenation (I and Br) of pyrazoles 1a, 3a and 4a gave halopyrazoles 5, 7–9, 11, 12. Reactivity differences between 1a, 3a and 4a, and the failure of 2a to give the expected halopyrazoles 6, 10 were explained using calculated relative energies of bromination, and inspection of frontier molecular orbitals. Utility of the prepared halides was demonstrated by a series of palladium-catalysed cross-coupling reactions.
Journal of Medicinal Chemistry | 2000
Lotte Bjerre Knudsen; Per F. Nielsen; Per Olaf Huusfeldt; Nils Langeland Johansen; Kjeld Madsen; Freddy Zimmerdahl Pedersen; Henning Thøgersen; and Michael Wilken; Henrik Agersø
Archive | 1997
Liselotte Bjerre Knudsen; Per Olaf Huusfeldt; Per F. Nielsen
Archive | 1999
Liselotte Bjerre Knudsen; Per Olaf Huusfeldt; Per F. Nielsen; Niels C. Kaarsholm; Helle Birk Olsen; Søren E. Bjørn; Freddy Zimmerdahl Pedersen; Kjeld Madsen
Archive | 1999
Liselotte Bjerre Knudsen; Per Olaf Huusfeldt; Per F. Nielsen; Kjeld Madsen
Archive | 1999
Liselotte Bjerre Knudsen; Per Olaf Huusfeldt; Per F. Nielsen; Kjeld Madsen
Archive | 1999
Liselotte Bjerre Knudsen; Per Olaf Huusfeldt
Archive | 1999
Liselotte Bjerre Knudsen; Per Olaf Huusfeldt; Per F. Nielsen; Niels C. Kaarsholm; Helle Birk Olsen; Søren E. Bjørn