4 research outputs found
Discovery of <i>N</i>‑Alkyl Piperazine Side Chain Based CXCR4 Antagonists with Improved Drug-like Properties
A novel
series of CXCR4 antagonists with piperidinyl and piperazinyl
alkylamine side chains designed as butyl amine replacements are described.
Several of these compounds showed similar activity to the parent compound
TIQ-15 (<b>5</b>) in a SDF-1 induced calcium flux assay. Preliminary
structure–activity relationship investigations led us to identify
a series containing <i>N</i>-propyl piperazine side chain
analogs exemplified by <b>16</b> with improved off-target effects
as measured in a muscarinic acetylcholine receptor (mAChR) calcium
flux assay and in a limited drug safety panel screen. Further efforts
to explore SAR and optimize drug properties led to the identification
of the <i>N</i>′-ethyl-<i>N</i>-propyl-piperazine
tetrahydroisoquinoline derivative <b>44</b> and the <i>N</i>-propyl-piperazine benzimidazole compound <b>37</b>, which gave the best overall profiles with no mAChR or CYP450 inhibition,
good permeability in PAMPA assays, and metabolic stability in human
liver microsomes
Synthesis of Novel Tetrahydroisoquinoline CXCR4 Antagonists with Rigidified Side-Chains
A structure–activity
relationship study of potent TIQ15-derived
CXCR4 antagonists is reported. In this investigation, the TIQ15 side-chain
was constrained to improve its drug properties. The cyclohexylamino
congener <b>15a</b> was found to be a potent CXCR4 inhibitor
(IC<sub>50</sub> = 33 nM in CXCL12-mediated Ca<sup>2+</sup> flux)
with enhanced stability in liver microsomes and reduced inhibition
of CYP450 (2D6). The improved CXCR4 antagonist <b>15a</b> has
potential therapeutic application as a single agent or combinatory
anticancer therapy
Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties
CXCR4 is a seven-transmembrane
receptor expressed by hematopoietic
stem cells and progeny, as well as by ≥48 different cancers
types. CXCL12, the only chemokine ligand of CXCR4, is secreted within
the tumor microenvironment, providing sanctuary for CXCR4<sup>+</sup> tumor cells from immune surveillance and chemotherapeutic elimination
by (1) stimulating prosurvival signaling and (2) recruiting CXCR4<sup>+</sup> immunosuppressive leukocytes. Additionally, distant CXCL12-rich
niches attract and support CXCR4<sup>+</sup> metastatic growths. Accordingly,
CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival
signaling, recondition the CXCR4<sup>+</sup> leukocyte infiltrate
from immunosuppressive to immunoreactive, and inhibit CXCR4<sup>+</sup> cancer cell metastasis. Current small molecule CXCR4 antagonists
suffer from poor oral bioavailability and off-target liabilities.
Herein, we report a series of novel tetrahydroÂisoquinoline-containing
CXCR4 antagonists designed to improve intestinal absorption and off-target
profiles. Structure–activity relationships regarding CXCR4
potency, intestinal permeability, metabolic stability, and cytochrome
P450 inhibition are presented
Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms
JAK2 kinase inhibitors are a promising
new class of agents for
the treatment of myeloproliferative neoplasms and have potential for
the treatment of other diseases possessing a deregulated JAK2-STAT
pathway. X-ray structure and ADME guided refinement of C-4 heterocycles
to address metabolic liability present in dialkylthiazole <b>1</b> led to the discovery of a clinical candidate, BMS-911543 (<b>11</b>), with excellent kinome selectivity, <i>in vivo</i> PD activity, and safety profile