Ballerup, Denmark
Ballerup, Denmark

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Grue-Sorensen G.,Chemical Research | Liang X.,Chemical Research | Mansson K.,Chemical Research | Vedso P.,Chemical Research | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Ingenol 3-benzoates were investigated with respect to chemical stability, pro-inflammatory effects, cell death induction and PKCδ activation. A correlation between structure, chemical stability and biological activity was found and compared to ingenol mebutate (ingenol 3-angelate) used for field treatment of actinic keratosis. We also provided further support for involvement of PKCδ for induction of oxidative burst and cytokine release. Molecular modeling and dynamics calculations corroborated the essential interactions between key compounds and C1 domain of PKCδ. © 2013 Elsevier Ltd. All rights reserved.


Berlin M.,Chemical Research | Lee Y.J.,Chemical Research | Boyce C.W.,Chemical Research | Wang Y.,Chemical Research | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Structural features of the substituted 4-piperidinyl urea analogs 1, responsible for the H3 antagonist activity, have been identified. Structure-activity relationship of the H3 receptor affinity, hERG ion channel inhibitory activity and their separation is described. Preliminary pharmacokinetic evaluation of the compounds of the series is addressed. © 2010 Elsevier Ltd. All rights reserved.


Sasmal P.K.,Dr. Reddys Laboratories Ltd | Sasmal S.,Dr. Reddys Laboratories Ltd | Rao P.T.,Dr. Reddys Laboratories Ltd | Venkatesham B.,Dr. Reddys Laboratories Ltd | And 13 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. © 2010 Elsevier Ltd. All rights reserved.


Sasmal S.,Dr. Reddys Laboratories Ltd | Balaji G.,Dr. Reddys Laboratories Ltd | Kanna Reddy H.R.,Dr. Reddys Laboratories Ltd | Balasubrahmanyam D.,Dr. Reddys Laboratories Ltd | And 16 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the β2-adrenergic receptor, including extracellular loops, were developed and used to guide the design. © 2012 Elsevier Ltd. All rights reserved.


Hogberg T.,Chemical Research | Frimurer T.M.,Copenhagen University | Sasmal P.K.,Dr. Reddys Laboratories Ltd.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes investigated in efforts to overcome hERG liabilities while having orally active, potent and selective compounds with sufficient brain penetration. A chemometric comparison of ∼2000 diverse MCHR1 and ∼1000 diverse hERG ligands underline the structural similarities. A binding pocket analysis of a MCHR1 model and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design. © 2012 Elsevier Ltd. All rights reserved.


Liang X.,Chemical Research | Grue-Sorensen G.,Chemical Research | Petersen A.K.,API Development | Hogberg T.,Chemical Research
Synlett | Year: 2012

A high-yielding method was developed for the preparation of ingenol 3-angelate (PEP005, ingenol mebutate) via the corresponding 5,20-acetonide without concomitant isomerization of the angelate (Z-form) to the corresponding tiglate (E-form). The general scope of the stereoconservative esterification method was further evaluated on several different alcohols, giving the angelates in up to quantitative yield without isomerization to the tiglate. © Georg Thieme Verlag KG Stuttgart · New York.


Szalai K.K.,Pharmacological and Drug Safety Research | Beke G.,Chemical Research | Eles J.,Chemical Research | Kitka T.,Pharmacological and Drug Safety Research | And 4 more authors.
Recent Patents on CNS Drug Discovery | Year: 2014

Today, the ‘obesity pandemic’ is one of the biggest health issues around the world. Melanin-concentrating hormone (MCH), a hypothalamic neuropeptide, is one of the most potent, central stimulators of feeding and it also attenuates energy expenditure. Inhibitions of the MCH receptor, the melanin-concentrating hormone receptor-1 (MCHR1), has attracted considerable attention as a potential anti-obesity drug, during the last decade. Now, there are a large number of MCHR1 antagonists, pharmacological tools and clinical drug candidates that can provide clues to develop new structures with high potency and good pharmacokinetic profile. The function of MCHR1 in energy homeostasis, obesity, metabolic syndrome, mood disorders and inflammatory bowel disease is discussed. Relevant clinical trials and patent background information of the MCHR1 antagonists over the last 4 years are also reviewed. © 2014 Bentham Science Publishers.


Liang X.,Chemical Research | Grue-Sorensen G.,Chemical Research | Mansson K.,Chemical Research | Vedso P.,Chemical Research | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

Ingenol mebutate is the active ingredient in Picato® a new drug for the treatment of actinic keratosis. A number of derivatives related to ingenol mebutate were prepared by chemical synthesis from ingenol with the purpose of investigating the SAR and potency in assays relating to pro-inflammatory effects (induction of PMN oxidative burst and keratinocyte cytokine release), the potential of cell death induction, as well as the chemical stability. By modifications of the ingenol scaffold several prerequisites for activity were identified. The chemical stability of the compounds could be linked to an acyl migration mechanism. We were able to find analogues of ingenol mebutate with comparable in vitro properties. Some key features for potent and more stable ingenol derivatives have been identified. © 2013 Elsevier Ltd. All rights reserved.


PubMed | CSIC - Biological Research Center, Chemical Research and Product Reprofiling
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2013

Ingenol 3-benzoates were investigated with respect to chemical stability, pro-inflammatory effects, cell death induction and PKC activation. A correlation between structure, chemical stability and biological activity was found and compared to ingenol mebutate (ingenol 3-angelate) used for field treatment of actinic keratosis. We also provided further support for involvement of PKC for induction of oxidative burst and cytokine release. Molecular modeling and dynamics calculations corroborated the essential interactions between key compounds and C1 domain of PKC.


PubMed | Chemical Research
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2012

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes investigated in efforts to overcome hERG liabilities while having orally active, potent and selective compounds with sufficient brain penetration. A chemometric comparison of 2000 diverse MCHR1 and 1000 diverse hERG ligands underline the structural similarities. A binding pocket analysis of a MCHR1 model and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design.

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