Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
Lysophosphatidic
acid (LPA) is a bioactive lipid mediator that
elicits a number of biological functions, including smooth muscle
contraction, cell motility, proliferation, and morphological change.
LPA is endogenously produced by autotaxin (ATX) from extracellular
lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal
chemistry effort to identify a novel and highly potent ATX inhibitor,
ONO-8430506 (20), with good oral availability. To enhance
the enzymatic ATX inhibitory activity, we designed several compounds
by structurally comparing our hit compound with the endogenous ligand
LPC. Further optimization to improve the pharmacokinetic profile and
enhance the ATX inhibitory activity in human plasma resulted in the
identification of ONO-8430506 (20), which enhanced the
antitumor effect of paclitaxel in a breast cancer model.
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