43001-25-8Relevant articles and documents
Systematic Variation of Pyrrolobenzodiazepine (PBD)-Dimer Payload Physicochemical Properties Impacts Efficacy and Tolerability of the Corresponding Antibody-Drug Conjugates
Staben, Leanna R.,Chen, Jinhua,Cruz-Chuh, Josefa dela,Del Rosario, Geoff,Go, Mary Ann,Guo, Jun,Khojasteh, S. Cyrus,Kozak, Katherine R.,Li, Guangmin,Ng, Carl,Lewis Phillips, Gail D.,Pillow, Thomas H.,Rowntree, Rebecca K.,Wai, John,Wei, BinQing,Xu, Keyang,Xu, Zijin,Yu, Shang-Fan,Zhang, Donglu,Dragovich, Peter S.
, p. 9603 - 9622 (2020/10/19)
Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody-drug conjugates (ADCs), and many examples are currently in clinical development. In order to further explore this ADC payload class, the physicochemical properties of various PBD-dimer molecules were modified by the systematic introduction of acidic and basic moieties into their chemical structures. The impact of these changes on DNA binding, cell membrane permeability, and in vitro antiproliferation potency was, respectively, determined using a DNA alkylation assay, PAMPA assessments, and cell-based cytotoxicity measurements conducted with a variety of cancer lines. The modified PBD-dimer compounds were subsequently incorporated into CD22-targeting ADCs, and these entities were profiled in a variety of in vitro and in vivo experiments. The introduction of a strongly basic moiety into the PBD-dimer scaffold afforded a conjugate with dramatically worsened mouse tolerability properties relative to ADCs derived from related payloads, which lacked the basic group.
Asymmetric synthesis of 12-hydroxyheptadecatrienoic acid and its 5,6-dihydro- and 14,15-dehydro-derivatives
Kobayashi, Yuichi,Morita, Masao,Ogawa, Narihito,Kondo, Daiki,Tojo, Toshifumi
, p. 10667 - 10673 (2016/11/30)
Natural 12-hydroxyheptadecatrienoic acid (12-HHT) with an S configuration was synthesised by a Suzuki-Miyaura coupling of C10-C17 iodo alcohol with C1-C9 vinylborane. The iodo alcohol was synthesised by utilising Sharpless asymmetric epoxidation of the corresponding trimethylsilyl alcohol. The method yielded more than 100 mg of 12-HHT. Similarly, syntheses of 5,6-dihydro- and 14,15-dehydro derivatives of 12-HHT, known as HHD and HHTE, respectively, were completed in a stereoselective manner.
INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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Paragraph 0223, (2016/10/06)
The present invention provides compounds of Formula Ia and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and conditions associated with excessive salt and water retention.
