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LIM kinase inhibitors

A kinase, C1-C6 technology, applied in the field of LIM kinase inhibitors, can solve the problem of no small molecule Limk inhibitors reported in the literature

Inactive Publication Date: 2019-03-15
富荣吉有限责任公司
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  • Claims
  • Application Information

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Problems solved by technology

[0008] To our knowledge, there are few literatures reporting small molecule Limk inhibitors

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[0121] illustrate

[0122] Our group reported a novel pyrazole-phenylurea skeleton 1( figure 1 ) as a potent and selective Rho kinase (ROCK) inhibitor that has a reducing effect on severe intraocular pressure (IOP) in rat eyes. 41,42 Compound 1 has low Limk inhibition (IC50>10 μM) in count-screen studies. However, SAR studies showed that substitution of the hinge-binding moiety pyrazole in 1 with 4-yl-pyrrolopyrimidine (compound 2) significantly reduced its ROCK-II affinity (ROCK-III C50 = 188 nM of 2 vs. 2 nM of 1)). Compound 2, on the other hand, achieved modest Limk1 inhibition (Limk1 IC50 = 642 nM vs. 10 μM of 1), revealing an interesting hinge-binder-dependent kinase selectivity of this phenylurea-based scaffold. Further modification of compound 2 at its urea terminal side resulted in compound 3 ( figure 1), which has an even weaker ROCK-II affinity (IC 50 =1365 nM) but improves Limk1 biochemical capacity (IC 50 =201 nM). Interestingly, the 4-yl-pyrrolopyrimidine mo...

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Abstract

A dynamic actin cytoskeleton is necessary for viral entry, intracellular migration, and virion release. For the human immunodeficiency virus (HIV), during viral entry, the virus triggers early actin activity through hijacking chemokine coreceptor signaling, which activates a viral dependency host factor cofilin and its kinase, the LIM domain kinase (LIMK). Although knockdown of human LIMK1 with siRNA inhibits HIV infection, no specific small molecule inhibitor of LIMK is available. Here we describe the design and development of novel classes of small molecule inhibitors of human LIMK, based ondifferent molecular scaffolds, for inhibiting infection by HIV, Ebola, and other viruses. Compounds of the invention can also be used for treatment of sexually transmitted diseases such as Herpes andChlamydia.

Description

[0001] Statement of Government Support [0002] This invention was made with government support under EY021799 awarded by the National Institutes of Health. The government has certain rights in this invention. [0003] cross reference [0004] This application claims the benefit of U.S. Provisional Application No. 62 / 338,040, filed May 18, 2016, the contents of which are hereby incorporated by reference in their entirety. It is known that color drawings and photographs are not accepted for international applications. The public is directed to the U.S. Patent Application Information Retrieval (PAIR) website, which, when searching for U.S. Provisional Application No. 62 / 338,040, filed May 18, 2016, provides the public with access to color versions of the drawings of this application. technical field Background technique [0005] LIM kinase (Limk) is a serine / threonine protein kinase. The two isoforms are LIM kinase 1 (LIMK1, Limk1) and LIM kinase 2 (LIMK2, Limk2) 1-4 . L...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519C07D487/00
CPCA61K31/519C07D487/04
Inventor 冯扬波吴云涛
Owner 富荣吉有限责任公司
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