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Sleep Initiation and Maintenance Disorders: HELP
Articles by Wilna J. Moree
Based on 8 articles published since 2008
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Between 2008 and 2019, Wilna J. Moree wrote the following 8 articles about Sleep Initiation and Maintenance Disorders.
 
+ Citations + Abstracts
1 Review The expanding role of H1 antihistamines: a patent survey of selective and dual activity compounds 2005-2010. 2010

Beaton, Graham / Moree, Wilna J. ·Drug Discovery Consultant. beaton.graham@gmail.com ·Expert Opin Ther Pat · Pubmed #20716024.

ABSTRACT: IMPORTANCE OF THE FIELD: Histamine plays a key role in physiological processes through its interaction with H(1-4) histamine receptors. The H(1) receptor is a key element in the pathophysiology of allergic responses. H(1) antihistamine use is a key strategy for therapy in allergy. AREAS COVERED IN THIS REVIEW: Several new chemical entities with improved efficacy in allergic disease have been pursued. Addition of multiple antagonist activities in single compounds has been the focus of current research. Involvement of the H(1) receptor in sleep has led to the evaluation of new compounds as sedative hypnotics. WHAT THE READER WILL GAIN: In all, 57 patents detail the evolution of new chemical entities. Dual H(1)-CC-chemokine receptor-3 and H(1)-H(3) antagonists have entered the clinic for allergic indications. Efforts to develop H(1) antihistamines as sedative hypnotics have increased, with several compounds entering the clinic. The dual H(1)-5-HT(2A) antagonist doxepin has been approved for sleep disorders while another compound is currently in clinical trials. TAKE HOME MESSAGE: The development of multiple activity H(1) antihistamines in allergy has met with limited success due in part to a competitive commercial environment. New sedative hypnotics may show potential but will need to demonstrate significant benefits in an increasingly competitive landscape.

2 Article Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H₁-antihistamines for insomnia. 2012

Ravula, Satheesh Babu / Yu, Jinghua / Tran, Joe A / Arellano, Melissa / Tucci, Fabio C / Moree, Wilna J / Li, Bin-Feng / Petroski, Robert E / Wen, Jianyun / Malany, Siobhan / Hoare, Samuel R J / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. satheesh.ravula@gmail.com ·Bioorg Med Chem Lett · Pubmed #22153347.

ABSTRACT: The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.

3 Article Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia. 2010

Moree, Wilna J / Li, Bin-Feng / Zamani-Kord, Said / Yu, Jinghua / Coon, Timothy / Huang, Charles / Marinkovic, Dragan / Tucci, Fabio C / Malany, Siobhan / Bradbury, Margaret J / Hernandez, Lisa M / Wen, Jianyun / Wang, Hua / Hoare, Samuel R J / Petroski, Robert E / Jalali, Kayvon / Yang, Chun / Sacaan, Aida / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. wilna.moree@gmail.com ·Bioorg Med Chem Lett · Pubmed #20800486.

ABSTRACT: Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.

4 Article The discovery and structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles as selective, CNS penetrating H1-antihistamines for insomnia. 2010

Lavrador-Erb, Karine / Ravula, Satheesh Babu / Yu, Jinghua / Zamani-Kord, Said / Moree, Wilna J / Petroski, Robert E / Wen, Jianyun / Malany, Siobhan / Hoare, Samuel R J / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. ·Bioorg Med Chem Lett · Pubmed #20347297.

ABSTRACT: A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H(1)-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H(1)-antihistamines.

5 Article Selectivity profiling of novel indene H(1)-antihistamines for the treatment of insomnia. 2010

Li, Bin-Feng / Moree, Wilna J / Yu, Jinghua / Coon, Timothy / Zamani-Kord, Said / Malany, Siobhan / Jalali, Kayvon / Wen, Jianyun / Wang, Hua / Yang, Chun / Hoare, Samuel R J / Petroski, Robert E / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, San Diego, CA 92130, USA. ·Bioorg Med Chem Lett · Pubmed #20227880.

ABSTRACT: A series of indene analogs of the H(1)-antihistamine (-)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H(1)-antihistamines with desirable selectivity over CYP enzymes, the M(1) muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.

6 Article Novel benzothiophene H1-antihistamines for the treatment of insomnia. 2010

Moree, Wilna J / Jovic, Florence / Coon, Timothy / Yu, Jinghua / Li, Bin-Feng / Tucci, Fabio C / Marinkovic, Dragan / Gross, Raymond S / Malany, Siobhan / Bradbury, Margaret J / Hernandez, Lisa M / O'Brien, Zhihong / Wen, Jianyun / Wang, Hua / Hoare, Samuel R J / Petroski, Robert E / Sacaan, Aida / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. wilna.moree@gmail.com ·Bioorg Med Chem Lett · Pubmed #20188547.

ABSTRACT: SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.

7 Article Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia. 2009

Moree, Wilna J / Li, Bin-Feng / Jovic, Florence / Coon, Timothy / Yu, Jinghua / Gross, Raymond S / Tucci, Fabio / Marinkovic, Dragan / Zamani-Kord, Said / Malany, Siobhan / Bradbury, Margaret J / Hernandez, Lisa M / O'Brien, Zhihong / Wen, Jianyun / Wang, Hua / Hoare, Samuel R J / Petroski, Robert E / Sacaan, Aida / Madan, Ajay / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, California 92130, USA. ·J Med Chem · Pubmed #19663387.

ABSTRACT: Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.

8 Article Brain-penetrating 2-aminobenzimidazole H(1)-antihistamines for the treatment of insomnia. 2009

Coon, Timothy / Moree, Wilna J / Li, Binfeng / Yu, Jinghua / Zamani-Kord, Said / Malany, Siobhan / Santos, Mark A / Hernandez, Lisa M / Petroski, Robert E / Sun, Aixia / Wen, Jenny / Sullivan, Sue / Haelewyn, Jason / Hedrick, Michael / Hoare, Samuel J / Bradbury, Margaret J / Crowe, Paul D / Beaton, Graham. ·Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. ·Bioorg Med Chem Lett · Pubmed #19553115.

ABSTRACT: The benzimidazole core of the selective non-brain-penetrating H(1)-antihistamine mizolastine was used to identify a series of brain-penetrating H(1)-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain-penetrating H(1)-antihistamines were identified and in vivo efficacy was demonstrated in a rat EEG/EMG model. Further optimization focused on strategies to attenuate an identified hERG liability, leading to the discovery of 4i with a promising in vitro profile.