Publications by authors named "K Ahrendt"

13 Publications

Triggering receptor expressed on myeloid cells 1 and 2 in patients with chronic maxillary sinusitis.

Bratisl Lek Listy 2021 ;122(6):391-395

Purpose: Chronic sinusitis can result from variable types of immune-mediated process, whose pathogenesis is not fully understood. Triggering receptors expressed on myeloid cells 1 and 2 (TREM-1, TREM-2) are involved in myeloid cell activation enabling these cells to fine-tune the inflammatory response, which may have an impact on subsequent adaptive immunity and may be the key factor in pathogenesis. The aim of the study was to analyse soluble TREM-1 and TREM-2 molecules in maxillary sinus lavage fluid and compare the defined subgroups selected from patients with chronic sinusitis with/without nasal polyps and allergy (asthma and allergic rhinitis).

Methods: The levels of soluble TREM-1 and TREM-2 were measured by Elisa test in a cohort of patients with chronic maxillary sinusitis (n=45). We compared subgroups of patients with nasal polyps (n=33) and allergy (n=25: inclusive of asthma (n=11) and allergic rhinitis (n=14)) with the control group of patients without nasal polyps (n=13), and without allergy (n=21).

Results: The study did not prove the difference between subgroups with and without nasal polyps. The levels of soluble TREM-1 did not differ significantly between patients with allergy (asthma and allergic rhinitis) and the control group without allergy (p=0.4804). The levels of soluble TREM-2 were significantly higher in patients with allergy (p=0.0028), asthma (p=0.0103) and allergic rhinitis (p=0.0137) as compared with the control group.

Conclusion: Our results suggest the role of TREM-2‑mediated activation of myeloid cells in chronic sinusitis accompanied by allergy, asthma, and allergic rhinitis (Tab. 6, Ref. 25).
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http://dx.doi.org/10.4149/10.4149/BLL_2021_065DOI Listing
May 2021

A noncompetitive inhibitor for Mycobacterium tuberculosis's class IIa fructose 1,6-bisphosphate aldolase.

Biochemistry 2014 Jan 24;53(1):202-13. Epub 2013 Dec 24.

Department of Chemistry and Biochemistry, University of Denver , Denver, Colorado 80208, United States.

Class II fructose 1,6-bisphosphate aldolase (FBA) is an enzyme critical for bacterial, fungal, and protozoan glycolysis/gluconeogenesis. Importantly, humans lack this type of aldolase, having instead a class I FBA that is structurally and mechanistically distinct from class II FBAs. As such, class II FBA is considered a putative pharmacological target for the development of novel antibiotics against pathogenic bacteria such as Mycobacterium tuberculosis, the causative agent for tuberculosis (TB). To date, several competitive class II FBA substrate mimic-styled inhibitors have been developed; however, they lack either specificity, potency, or properties that limit their potential as possible therapeutics. Recently, through the use of enzymatic and structure-based assisted screening, we identified 8-hydroxyquinoline carboxylic acid (HCA) that has an IC50 of 10 ± 1 μM for the class II FBA present in M. tuberculosis (MtFBA). As opposed to previous inhibitors, HCA behaves in a noncompetitive manner, shows no inhibitory properties toward human and rabbit class I FBAs, and possesses anti-TB properties. Furthermore, we were able to determine the crystal structure of HCA bound to MtFBA to 2.1 Å. HCA also demonstrates inhibitory effects for other class II FBAs, including pathogenic bacteria such as methicillin-resistant Staphylococcus aureus. With its broad-spectrum potential, unique inhibitory characteristics, and flexibility of functionalization, the HCA scaffold likely represents an important advancement in the development of class II FBA inhibitors that can serve as viable preclinical candidates.
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http://dx.doi.org/10.1021/bi401022bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167715PMC
January 2014

Imidazo[4,5-b]pyridine inhibitors of B-Raf kinase.

Bioorg Med Chem Lett 2013 Nov 29;23(21):5896-9. Epub 2013 Aug 29.

Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. Electronic address:

This Letter details the synthesis and evaluation of imidazo[4,5-b]pyridines as inhibitors of B-Raf kinase. These compounds bind in a DFG-in, αC-helix out conformation of B-Raf, which is a binding mode associated with significant kinase selectivity. Structure-activity relationship studies involved optimization of the ATP-cleft binding region of these molecules, and led to compound 23, an inhibitor with excellent enzyme/cell potency, and kinase selectivity.
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http://dx.doi.org/10.1016/j.bmcl.2013.08.086DOI Listing
November 2013

The discovery of potent and selective pyridopyrimidin-7-one based inhibitors of B-RafV600E kinase.

Bioorg Med Chem Lett 2012 May 10;22(10):3387-91. Epub 2012 Apr 10.

Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.

Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies.
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http://dx.doi.org/10.1016/j.bmcl.2012.04.015DOI Listing
May 2012

Pyrazolopyridine inhibitors of B-Raf(V600E). Part 3: an increase in aqueous solubility via the disruption of crystal packing.

Bioorg Med Chem Lett 2012 Jan 10;22(2):912-5. Epub 2011 Dec 10.

Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.

A single crystal was obtained of a lead B-Raf(V600E) inhibitor with low aqueous solubility. The X-ray crystal structure revealed hydrogen-bonded head-to-tail dimers formed by the pyrazolopyridine and sulfonamide groups of a pair of molecules. This observation suggested a medicinal chemistry strategy to disrupt crystal packing and reduce the high crystal lattice energy of alternative inhibitors. Both a bulkier group at the interface of the dimer and an out-of-plane substituent were required to decrease the compound's melting point and increase aqueous solubility. These substituents were selected based on previously developed structure-activity relationships so as to concurrently maintain good enzymatic and cellular activity against B-Raf(V600E).
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http://dx.doi.org/10.1016/j.bmcl.2011.12.030DOI Listing
January 2012
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