- Heteroaromatic Inhibitors of the Astacin Proteinases Meprin α, Meprin β and Ovastacin Discovered by a Scaffold-Hopping Approach
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Astacin metalloproteinases, in particular meprins α and β, as well as ovastacin, are emerging drug targets. Drug-discovery efforts have led to the development of the first potent and selective inhibitors in the last few years. However, the most recent compounds are based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or decreased potency due to the entropic penalty upon binding to the target. Thus, the aim of this study was to discover novel conformationally constrained scaffolds as starting points for further inhibitor optimization. Shifting from flexible tertiary amines to rigid heteroaromatic cores resulted in a boost in inhibitory activity. Moreover, some compounds already exhibited higher activity against individual astacin proteinases compared to recently reported inhibitors and also a favorable off-target selectivity profile, thus qualifying them as very suitable chemical probes for target validation.
- Tan, Kathrin,J?ger, Christian,K?rschgen, Hagen,Geissler, Stefanie,Schlenzig, Dagmar,Buchholz, Mirko,St?cker, Walter,Ramsbeck, Daniel
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supporting information
p. 976 - 988
(2020/12/25)
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- HETEROAROMATIC INHIBITORS OF ASTACIN PROTEINASES
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The present invention relates to novel hydroxamic acid derivatives useful as inhibitors of astacin metalloproteinases, in particular procollagen C-proteinase (PCP) enzymes, meprins, ovastacin and/or nematode astacins; more particularly human or mammalian
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Paragraph 0111; 0113
(2020/12/22)
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- Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders
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Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clinical trials.
- Mikami, Satoshi,Nakamura, Shinji,Ashizawa, Tomoko,Nomura, Izumi,Kawasaki, Masanori,Sasaki, Shigekazu,Oki, Hideyuki,Kokubo, Hironori,Hoffman, Isaac D.,Zou, Hua,Uchiyama, Noriko,Nakashima, Kosuke,Kamiguchi, Naomi,Imada, Haruka,Suzuki, Noriko,Iwashita, Hiroki,Taniguchi, Takahiko
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p. 7677 - 7702
(2017/10/06)
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- NITROGENATED HETEROCYCLIC COMPOUND
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The present invention provides a compound having a PDE2A selective inhibitory action, which is useful as an agent for the prophylaxis or treatment of schizophrenia, Alzheimer's disease and the like. The present invention is a compound represented by the formula (1): wherein each symbol is as described in the specification, or a salt thereof.
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Paragraph 0515
(2015/03/28)
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- HETEROCYCLIC COMPOUND
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The present invention provides a compound having a PDE2A selective inhibitory action, which is useful as an agent for the prophylaxis or treatment of schizophrenia, Alzheimer's disease and the like. The present invention is a compound represented by the f
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Paragraph 0379; 0380
(2015/05/26)
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- SYNTHESES OF FUNCTIONALIZED N-(2-PYRIDYL)-α-AMINO ACIDS AND ESTERS BY RING OPENING OF IMIDAZOPYRIDINE
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This report is devoted to the ring opening of the imidazole nucleus of functionalized imidazopyridines, by methanol in strong acid medium (HClO4) leading to esters of N-(2-pyridyl)-α-amino acids in which the heterocyclic moiety bears a functional g
- Doise, Muriel,Blondeau, Dominique,Sliwa, Henri
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p. 2079 - 2093
(2007/10/02)
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