Discovery and optimization of pyrazole amides as antagonists of CCR1

被引：3

作者：

Harcken, Christian ^{[1
]}

Sarko, Christopher ^{[1
]}

Mao, Can ^{[1
]}

Lord, John ^{[1
]}

Raudenbush, Brian ^{[1
]}

Razavi, Hossein ^{[1
]}

Liu, Pingrong ^{[1
]}

Swinamer, Alan ^{[1
]}

Disalvo, Darren ^{[1
]}

Lee, Thomas ^{[1
]}

Lin, Siqi ^{[2
]}

Kukulka, Alison ^{[2
]}

Grbic, Heather ^{[3
]}

Patel, Mita ^{[3
]}

Patel, Monica ^{[3
]}

Fletcher, Kim ^{[3
]}

Joseph, David ^{[3
]}

White, Della ^{[4
]}

Amodeo, Laura ^{[4
]}

Berg, Karen ^{[4
]}

Brown, Maryanne ^{[4
]}

Thomson, David S. ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharmaceut Inc, Med Chem Dept, 900 Ridgebury Rd,POB 368, Ridgefield, CT 06877 USA

[2] Boehringer Ingelheim Pharmaceut Inc, Compound Profiling Dept, 900 Ridgebury Rd,POB 368, Ridgefield, CT 06877 USA

[3] Boehringer Ingelheim Pharmaceut Inc, Drug Discovery Support Dept, 900 Ridgebury Rd,POB 368, Ridgefield, CT 06877 USA

[4] Boehringer Ingelheim Pharmaceut Inc, Immunol & Resp Dis Res Dept, 900 Ridgebury Rd,POB 368, Ridgefield, CT 06877 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 03期

关键词：

Chemokine receptors; CCR1; Pyrazole; HTS hit; Development candidate; CHEMOKINE RECEPTORS; PLUS METHOTREXATE; ARTHRITIS; EFFICACY; PHARMACOKINETICS; BLOCKADE; TARGETS; MLN3897; SAFETY; POTENT;

D O I：

10.1016/j.bmcl.2018.11.015

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.

引用

页码：435 / 440

页数：6

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