422280-37-3Relevant articles and documents
Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1)
Abeywickrema, Pravien,Andrews, Christine,Augustin, Martin,Bennett, David Jonathan,Cheng, Mangeng,Cowley, Phillip,Curran, Patrick,Fradera, Xavier,Geda, Prasanthi,Han, Yongxin,Heo, Mee Ra,Joshi, Elizabeth M.,Knemeyer, Ian,Lesburg, Charles A.,Lim, Jongwon,McGowan, Meredeth A.,Miller, J. Richard,Nickbarg, Elliott B.,Otte, Karin,Sciammetta, Nunzio,Smotrov, Nadya,Song, Xuelei,Spacciapoli, Peter,Trewick, Sarah,Von K?enig, Konstanze,White, Catherine,Woo, Hyun,Yu, Wensheng,Zhou, Hua
, p. 550 - 557 (2020)
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1. While hit 1 possessed attractive cell-based potency, it suffered from a significant right-shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-based approach, including a focus on lowering AlogP98 via the strategic introduction of polar substitution, compound 13 was identified bearing a pyridyl oxetane core. Compound 13 demonstrated improved whole blood potency and solubility, and an improved pharmacokinetic profile resulting in a low predicted human dose.
Substituted alkanoic acids
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Page 36, (2010/02/05)
The invention is directed to physiologically active compounds of general formula (I): wherein:- represents (i) a saturated 3 to 6 membered carbocycle, optionally substituted by one or more alkyl groups, (ii) indanyl or (iii) a saturated 4 to 6 membered heterocyclic ring; R1 represents R3Z1-Het- or R4N(R5)—C(═O)—NH—Ar1—; L1 represents an —R6—R7— linkage; R2 represents hydrogen, halogen, lower alkyl or lower alkoxy; L2 represents an alkylene linkage; Y is carboxy or an acid bioisostere; and their corresponding N-oxides or prodrugs, and pharmaceutically acceptable salts and solvates of such compounds and their corresponding N-oxides or prodrugs. Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (α4β1).
