Yli-Kauhaluoma J

References (5)

Title : Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12 - Ahonen_2023_ACS.Med.Chem.Lett_14_1404
Author(s) : Ahonen TJ , Ng CP , Farinha B , Almeida B , Victor BL , Reynolds C , Kalso E , Yli-Kauhaluoma J , Greaves J , Moreira VM
Ref : ACS Med Chem Lett , 14 :1404 , 2023
Abstract : 12-Thiazole abietanes are highly selective reversible inhibitors of hABHD16A that could potentially alleviate neuroinflammation. In this study, we used synthetic chemistry, competitive activity-based protein profiling, and computational methodologies to try to establish relevant structural determinants of activity and selectivity of this class of compounds for inhibiting ABHD16A over ABHD12. Five compounds significantly inhibited hABHD16A but also very efficiently discriminated between inhibition of hABHD16A and hABHD12, with compound 35 being the most effective, at 100 microM (55.1 +/- 8.7%; p < 0.0001). However, an outstanding switch in the selectivity toward ABHD12 was observed in the presence of a ring A ester, if the C2' position of the thiazole ring possessed a 1-hydroxyethyl group, as in compound 28. Although our data were inconclusive as to whether the observed enzyme inhibition is allosteric or not, we anticipate that the structure-activity relationships presented herein will inspire future drug discovery efforts in this field.
ESTHER : Ahonen_2023_ACS.Med.Chem.Lett_14_1404
PubMedSearch : Ahonen_2023_ACS.Med.Chem.Lett_14_1404
PubMedID: 37849541
Gene_locus related to this paper: human-ABHD12 , human-ABHD16A

Title : Utilizing PET and MALDI Imaging for Discovery of a Targeted Probe for Brain Endocannabinoid alpha\/beta-Hydrolase Domain 6 (ABHD6) - Mardon_2022_J.Med.Chem__
Author(s) : Mardon K , Patel JZ , Savinainen JR , Stimson DHR , Oyagawa CRM , Grimsey NL , Migotto MA , Njiru GFM , Hamilton BR , Cowin G , Yli-Kauhaluoma J , Vanduffel W , Blakey I , Bhalla R , Cawthorne C , Celen S , Bormans G , Thurecht KJ , Ahamed M
Ref : Journal of Medicinal Chemistry , : , 2022
Abstract : Multimodal imaging provides rich biological information, which can be exploited to study drug activity, disease associated phenotypes, and pharmacological responses. Here we show discovery and validation of a new probe targeting the endocannabinoid alpha/beta-hydrolase domain 6 (ABHD6) enzyme by utilizing positron emission tomography (PET) and matrix-assisted laser desorption/ionization (MALDI) imaging. [(18)F]JZP-MA-11 as the first PET ligand for in vivo imaging of the ABHD6 is reported and specific uptake in ABHD6-rich peripheral tissues and major brain regions was demonstrated using PET. A proof-of-concept study in nonhuman primate confirmed brain uptake. In vivo pharmacological response upon ABHD6 inhibition was observed by MALDI imaging. These synergistic imaging efforts used to identify biological information cannot be obtained by a single imaging modality and hold promise for improving the understanding of ABHD6-mediated endocannabinoid metabolism in peripheral and central nervous system disorders.
ESTHER : Mardon_2022_J.Med.Chem__
PubMedSearch : Mardon_2022_J.Med.Chem__
PubMedID: 36516997

Title : Discovery of 12-Thiazole Abietanes as Selective Inhibitors of the Human Metabolic Serine Hydrolase hABHD16A - Ahonen_2018_ACS.Med.Chem.Lett_9_1269
Author(s) : Ahonen TJ , Savinainen JR , Yli-Kauhaluoma J , Kalso E , Laitinen JT , Moreira VM
Ref : ACS Med Chem Lett , 9 :1269 , 2018
Abstract : Screening of an in-house library of compounds identified 12-thiazole abietanes as a new class of reversible inhibitors of the human metabolic serine hydrolase. Further optimization of the first hit compound lead to the 2-methylthiazole derivative 18, with an IC50 value of 3.4 +/- 0.2 muM and promising selectivity. ABHD16A has been highlighted as a new target for inflammation-mediated pain, although selective inhibitors of hABHD16A (human ABHD16A) have not yet been reported. Our study presents abietane-type diterpenoids as an attractive starting point for the design of selective ABHD16A inhibitors, which will contribute toward understanding the significance of hABHD16A inhibition in vivo.
ESTHER : Ahonen_2018_ACS.Med.Chem.Lett_9_1269
PubMedSearch : Ahonen_2018_ACS.Med.Chem.Lett_9_1269
PubMedID: 30613338
Gene_locus related to this paper: human-ABHD16A

Title : Discovery of Triterpenoids as Reversible Inhibitors of alpha\/beta-hydrolase Domain Containing 12 (ABHD12) - Parkkari_2014_PLoS.One_9_e98286
Author(s) : Parkkari T , Haavikko R , Laitinen T , Navia-Paldanius D , Rytilahti R , Vaara M , Lehtonen M , Alakurtti S , Yli-Kauhaluoma J , Nevalainen T , Savinainen JR , Laitinen JT
Ref : PLoS ONE , 9 :e98286 , 2014
Abstract : BACKGROUND: alpha/beta-hydrolase domain containing (ABHD)12 is a recently discovered serine hydrolase that acts in vivo as a lysophospholipase for lysophosphatidylserine. Dysfunctional ABHD12 has been linked to the rare neurodegenerative disorder called PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, cataract). In vitro, ABHD12 has been implicated in the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG). Further studies on ABHD12 function are hampered as no selective inhibitor have been identified to date. In contrast to the situation with the other endocannabinoid hydrolases, ABHD12 has remained a challenging target for inhibitor development as no crystal structures are available to facilitate drug design. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the unexpected discovery that certain triterpene-based structures inhibit human ABHD12 hydrolase activity in a reversible manner, the best compounds showing submicromolar potency. Based on structure activity relationship (SAR) data collected for 68 natural and synthetic triterpenoid structures, a pharmacophore model has been constructed. A pentacyclic triterpene backbone with carboxyl group at position 17, small hydrophobic substituent at the position 4, hydrogen bond donor or acceptor at position 3 accompanied with four axial methyl substituents was found crucial for ABHD12 inhibitor activity. Although the triterpenoids typically may have multiple protein targets, we witnessed unprecedented selectivity for ABHD12 among the metabolic serine hydrolases, as activity-based protein profiling of mouse brain membrane proteome indicated that the representative ABHD12 inhibitors did not inhibit other serine hydrolases, nor did they target cannabinoid receptors. CONCLUSIONS/SIGNIFICANCE: We have identified reversibly-acting triterpene-based inhibitors that show remarkable selectivity for ABHD12 over other metabolic serine hydrolases. Based on SAR data, we have constructed the first pharmacophore model of ABHD12 inhibitors. This model should pave the way for further discovery of novel lead structures for ABHD12 selective inhibitors.
ESTHER : Parkkari_2014_PLoS.One_9_e98286
PubMedSearch : Parkkari_2014_PLoS.One_9_e98286
PubMedID: 24879289
Gene_locus related to this paper: human-ABHD12

Title : Acetylcholinesterase inhibitory guided fractionation of Melissa officinalis L - Dastmalchi_2009_Bioorg.Med.Chem_17_867
Author(s) : Dastmalchi K , Ollilainen V , Lackman P , Boije af Gennas G , Dorman HJ , Jarvinen PP , Yli-Kauhaluoma J , Hiltunen R
Ref : Bioorganic & Medicinal Chemistry , 17 :867 , 2009
Abstract : The plant Melissa officinalis L. has been used traditionally in the treatment of cognitive dysfunction. Based on its traditional medicinal use, it was assessed for its clinical efficacy in mild to moderate Alzheimer's patients. The plant was effective in the management of the disease. Therefore, based on this result, a similar plant extract was prepared in order to be screened for bioactivities which are relevant in Alzheimer's disease therapy. The extract was recently screened for antioxidant activity and it showed a wide range of antioxidant properties. Another important bioactivity is acetylcholinesterase inhibition, which the extract was screened for in the current investigation. The extract was capable of inhibiting the enzyme in a time and dose-dependent manner. Activity of the extract at 10 min was estimated as 1.72+/-0.16 microg equivalents of physostigmine/mg of the extract. Acetylcholinesterase inhibitory guided fractionation of the extract was then carried out. Most of the fractions showed inhibitory activity and were more potent than the extract. The contents of the most potent fraction were identified as cis- and trans-rosmarinic acid isomers and a rosmarinic acid derivative using LC-DAD-ESI-MS and NMR methods.
ESTHER : Dastmalchi_2009_Bioorg.Med.Chem_17_867
PubMedSearch : Dastmalchi_2009_Bioorg.Med.Chem_17_867
PubMedID: 19070498