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

共 50 条

[21] Therapeutic potential of CCR1 antagonists for multiple myeloma
Karash, Angela R.
Gilchrist, Annette
FUTURE MEDICINAL CHEMISTRY, 2011, 3 (15) : 1889 - 1908
[22] Optimization of an Azaindazole Series of CCR1 Antagonists and Development of a Semicontinuous-Flow Synthesis
Harcken C.
Grant J.
Razavi H.
Marsini M.A.
Buono F.G.
Lorenz J.C.
Reeves J.T.
ACS Symposium Series, 2019, 1332 : 185 - 238
[23] The discovery of structurally novel CCR1 antagonists derived from a hydroxyethylene peptide isostere template
Kath, JC
DiRico, AP
Gladue, RP
Martin, WH
McElroy, EB
Stock, IA
Tylaska, LA
Zheng, DY
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (09) : 2163 - 2167
[24] Identification of novel series of human CCR1 antagonists
Xie, Yun Feng
Sircar, Ila
Lake, Kirk
Komandla, Mallareddy
Ligsay, Kathleen
Li, Jian
Xu, Kui
Parise, Jason
Schneider, Lisa
Huang, Dingqiu
Liu, Juping
Sakurai, Naoki
Barbosa, Miguel
Jack, Rick
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (06) : 2215 - 2221
[25] Design, synthesis, and discovery of a novel CCR1 antagonist
Naya, A
Sagara, Y
Ohwaki, K
Saeki, T
Ichikawa, D
Iwasawa, Y
Noguchi, K
Ohtake, N
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (09) : 1429 - 1435
[26] MEDI 207-Discovery of novel, orally available piperidine-containing CCR1 antagonists
Lu, Shou-Fu
Chou, Yuo-Ling
Lee, Wheeseong
Liang, Xiaolin
Phillips, Gary B.
Schlyer, Sabine
Wei, Robert G.
Xu, Jinlou
Yu, Hongyi
Ge, Xue Snow
Harirchian, Paymann
Ribeiro, Sofia
Subramanyam, Babu
Walters, Janette
Horuk, Richard
Kochanny, Monica J.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2006, 232
[27] Identification of highly specific nonpeptide antagonists of the CCR1 receptor.
Horuk, R
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2000, 219 : U62 - U62
[28] The discovery of BMS-457, a potent and selective CCR1 antagonist
Gardner, Daniel S.
Santella, Joseph B., III
Duncia, John V.
Carter, Percy H.
Dhar, T. G. Murali
Wu, Hong
Guo, Weiwei
Cavallaro, Cullen
Van Kirk, Katy
Yarde, Melissa
Briceno, Stephanie W.
Grafstrom, R. Robert
Liu, Richard
Patel, Sima R.
Tebben, Andrew J.
Camac, Dan
Khan, Javed
Watson, Andrew
Yang, Guchen
Rose, Anne
Foster, William R.
Cvijic, Mary Ellen
Davies, Paul
Hynes, John, Jr.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (13) : 3833 - 3840
[29] Assessing CCR1 Antagonists for Chemotaxis Inhibition in a Multiple Myeloma In Vitro Model
Echeverria, S. L.
Gilchrist, A.
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL, 2021, 57 (SUPPL 1) : S32 - S32
[30] Assessing CCR1 Antagonists for Chemotaxis Inhibition in a Multiple Myeloma in vitro Model
Echeverria, Stephanie
Gilchrist, Annette
FASEB JOURNAL, 2021, 35

← 1 2 3 4 5 →