Important Compound Classes
Title
Five Membered-Aminoheterocyclic and 5,6- or 6,6-Membered Bicyclic Aminoheterocyclic Inhibitors of ROCK for the Treatment of Heart Failure
Patent Application Number
WO 2019/014303 A1
Publication Date
January 17, 2019
Priority Application
US 62/531,590
Priority Date
July 12, 2017
Inventors
Pinto, D. J. P; Maishal, T. K.
Assignee Company
Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
Disease Area
Cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory diseases
Biological Target
Rho-Kinase (ROCK)
Summary
The invention in this patent application relates to monocyclic or bicydic aminoheterocydic compounds represented generally by formula I. These compounds are selective ROCK inhibitors and may be useful for the treatment of cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders.
Rho-Kinase, also known as Rho-associated kinase or Rho-associated, coiled-coil-containing protein kinase (ROCK) is a member of the serine-threonine protein kinase family. ROCK exists in two isoforms, ROCK1 and ROCK2. It has been identified as an effector molecule of RhoA, a small guanosine triphosphate (GTP)-binding protein (G protein) that plays a key role in multiple cellular signaling pathways. ROCK and RhoA are ubiquitously expressed across tissues.
Because of the involvement of ROCK in many cellular signaling pathways, its activities were subjects of numerous studies that underscore the importance of this kinase and its potential as a therapeutic target for the treatment of many diseases. The following are the highlights of the findings from some of these studies:
There is evidence of key roles played by Rho A/ROCK signaling pathway in several signal transduction initiated by a number of vasoactive factors. Many of these factors such as angiotensin II, urotensin II, endothelin-1, serotonin, norepinephrine, and platelet-derived growth factor (PDGF) have been implicated in the pathogenesis of cardiovascular disease.
Elevated ROCK expression and activity were observed in spontaneously hypertensive rats, thus suggesting a link between ROCK activities and the development of hypertension in these test animals. In addition, when three rat models of hypertension, including the spontaneously hypertensive rat, renal hypertensive rat, and deoxy cortisone acetate salt hypertensive rat models were treated with the known ROCK inhibitor Y-27632, their blood pressures were significantly decreased compared to those of control rats. These results confirmed a link between ROCK and hypertension.
The RhoA/ROCK signaling pathway is involved in a number of cellular functions such as Actin organization, cell adhesion, cell migration, and cytokinesis. It is also directly involved in regulating smooth muscle contraction. Activation of RhoA, in turn, activates ROCK to phosphorylate the myosin-binding subunit of myosin light chain (MLC) phosphatase, which inhibits the activity of the phosphatase and leads to contraction. Contraction of the smooth muscles in the vasculature increases blood pressure, leading to hypertension.
Gene transfer of a dominant negative form of ROCK following balloon injury in porcine femoral arteries caused the inhibition of neointimal formation. Similarly, the ROCK inhibitor Y-27632 suppressed neointimal formation in rats. A long-term treatment with the ROCK inhibitor fasudil in a porcine model of IL-1 beta-induced coronary stenosis progressively reduced coronary stenosis and promoted a regression of coronary constrictive remodeling. These findings suggest a link between ROCK and atherosclerosis.
The ROCK inhibitor fasudil reduced both the infarct size and neurologic deficit in a rat stroke model. Another ROCK inhibitor Y-27632 improved ventricular hypertrophy, fibrosis, and function in a model of congestive heart failure in Dahl salt-sensitive rats. These results suggested that ROCK inhibitors may potentially be useful in treating these cardiovascular conditions.
Animal and clinical studies have implicated ROCK in coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, pulmonary hypertension, angina, renal disease, and erectile dysfunction.
Inhibition of the RhoA/ROCK signaling pathway allows the formation of multiple competing lamellipodia that disrupt the productive migration of monocytes. Small molecule ROCK inhibitors suppressed monocyte chemoattractant protein-1 (MCP-1) mediated chemotaxis in vitro. The dependence of immune cell migration upon the RhoA/ROCK signaling pathway suggests additional potential benefit from inhibition of Rho Kinase in treatment of diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
Research has also determined that ROCK is overexpressed in cancer cells compared to normal cells. This overexpression was linked to metastasis, poor clinical outcome, and shorter survival of cancer patients. Thus, inhibition of ROCK may potentially be useful in treatment of cancer.
The above data have provided good evidence that ROCK inhibitors may be useful for the treatment of many cardiovascular diseases including hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, pulmonary hypertension, and angina. There is also potential for using ROCK inhibitors for the treatment of renal disease and erectile dysfunction and diseases resulting from smooth muscle hyper-reactivity including asthma and glaucoma.
Recent statistics on Heart Disease and Stroke from the 2012 update of the American Heart Association show that 32.8% of all deaths in the US resulted from cardiovascular diseases (CVD). About 33.5% of the US adult population suffer from hypertension, and an estimated 6.6 million US adults may have had heart failures in 2010. These statistics show that despite the large number of currently available CVD medications, such as diuretics, beta-blockers, angiotensin converting enzyme inhibitors, angiotensin blockers, and calcium channel blockers, CVD remained poorly controlled and resistant to current medications in many patients.
Therefore, novel and more effective CVD drugs are still needed. The use of ROCK inhibitors is promising and may address some of this need. While there are numerous reports of ROCK inhibitors under investigation, fasudil and ripasudil are the only marketed ROCK inhibitors at this time. Fasudil was approved 1995 in Japan (and then in China) as an IV-formulation for the treatment of cerebral vasospasm. Ripasudil was approved in Japan in 2014 as an eye drop formulation for the treatment of glaucoma and ocular hypertension. Thus, there remains a need for the discovery and development of new ROCK inhibitors, such as the compounds described in this patent application, that may potentially provide useful treatments of many diseases such as cardiovascular diseases, cancer, neurological diseases, renal diseases, fibrotic diseases, bronchial asthma, erectile dysfunction, and glaucoma.
Key Structures
The inventors described the structures
and methods of synthesis of 70 examples of formula I including the
following representative examples.
Biological Assay
ROCK inhibitory activity assay
Biological Data
The IC50 values for the
inhibition of ROCK2 in nm obtained from testing the above representative
examples are listed in the following table:
Recent Review Articles
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Shi J.; Wei L.. J. Cardiovasc. Pharmacol. 2013, 62 ( (4), ), 341–354.
The author declares no competing financial interest.