ACS Medicinal Chemistry Letters最新文献

This letter describes the structure-activity relationship studies of a voltage-gated sodium channel (VGSC) blocker SV188 guided by its docking model in the lacosamide binding site of Na_V1.7. Seventeen analogs of SV188 were designed, synthesized, and evaluated for whole cell I _Na blockade and cytotoxicity using metastatic medullary thyroid cancer cell line MZ-CRC-1. Three analogs exhibited improved I _Na blockade compared to SV188. Thirteen analogs showed reduced cytotoxicity compared to SV188. Three selected compounds were further evaluated for their cell invasion inhibition activities. All three compounds displayed cell invasion inhibitory activities that were better than those of SV188. The most promising lead compound IIB7 showed no cytotoxicity to MZ-CRC-1 cells up to 100 μM and inhibited VGSC-mediated cell invasion by 71% at 15 μM.

We report the optimization of a series of IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced a key compound 27 that displays potent and selective inhibition of IRAK1, IRAK4, and FLT3, reduced block of hERG, and good pharmacokinetic properties. In a mouse xenograft model of acute myeloid leukemia (AML), 27 produces survival prolongation superior to that of gilteritinib, the leading FDA-approved FLT3 inhibitor currently used to treat AML.

This letter describes the structure–activity relationship studies of a voltage-gated sodium channel (VGSC) blocker SV188 guided by its docking model in the lacosamide binding site of Na_V1.7. Seventeen analogs of SV188 were designed, synthesized, and evaluated for whole cell I_Na blockade and cytotoxicity using metastatic medullary thyroid cancer cell line MZ-CRC-1. Three analogs exhibited improved I_Na blockade compared to SV188. Thirteen analogs showed reduced cytotoxicity compared to SV188. Three selected compounds were further evaluated for their cell invasion inhibition activities. All three compounds displayed cell invasion inhibitory activities that were better than those of SV188. The most promising lead compound IIB7 showed no cytotoxicity to MZ-CRC-1 cells up to 100 μM and inhibited VGSC-mediated cell invasion by 71% at 15 μM.

We report the optimization of a series of IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced a key compound 27 that displays potent and selective inhibition of IRAK1, IRAK4, and FLT3, reduced block of hERG, and good pharmacokinetic properties. In a mouse xenograft model of acute myeloid leukemia (AML), 27 produces survival prolongation superior to that of gilteritinib, the leading FDA-approved FLT3 inhibitor currently used to treat AML.

Herein we describe our continuing work on the K₂P family of potassium ion channels with the chemical optimization of a selective and CNS penetrant series of TREK inhibitors, culminating in the discovery of ONO-TR-772 (VU6018042). From an HTS hit harboring a benzyl ether linker, SAR proved intractable until an acetylene linker was identified as an isosteric replacement. Robust SAR was then observed, and a key fluorination to enhance PK and CNS penetration provided ONO-TR-772 (VU6018042), a potent (TREK-1 IC₅₀ = 15 nM), selective (>10 μM versus other K₂P channels except TREK-2), and CNS penetrant (rat K _p = 0.98) TREK inhibitor. ONO-TR-772 (VU6018042) demonstrated robust efficacy in an MK-801 challenge NOR paradigm, with an MED of 10 mg/kg.

Herein we describe our continuing work on the K₂P family of potassium ion channels with the chemical optimization of a selective and CNS penetrant series of TREK inhibitors, culminating in the discovery of ONO-TR-772 (VU6018042). From an HTS hit harboring a benzyl ether linker, SAR proved intractable until an acetylene linker was identified as an isosteric replacement. Robust SAR was then observed, and a key fluorination to enhance PK and CNS penetration provided ONO-TR-772 (VU6018042), a potent (TREK-1 IC₅₀ = 15 nM), selective (>10 μM versus other K₂P channels except TREK-2), and CNS penetrant (rat K_p = 0.98) TREK inhibitor. ONO-TR-772 (VU6018042) demonstrated robust efficacy in an MK-801 challenge NOR paradigm, with an MED of 10 mg/kg.

Provided herein are novel compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma or COPD, and processes for preparing such compounds.

Provided herein are novel compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma or COPD, and processes for preparing such compounds.