Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA 1 ) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA 1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA 1 receptor agonist described so far (E max = 118%, EC 50 = 0.24 μM, K D = 19.6 nM; inactive at autotaxin and LPA 2−6 receptors). This compound induces characteristic LPA 1 -mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.
Hutchinson–Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the Lmna G609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.
Spinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA 2 ) has recently emerged as a new potential pharmacological approach to decrease SCI-associated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA 2 antagonists, among which compound 54 (UCM-14216) stands out as a potent and selective LPA 2 receptor antagonist ( E max = 90%, IC 50 = 1.9 μM, K D = 1.3 nM; inactive at LPA 1,3–6 receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA 2 -dependent manner, confirming the potential of LPA 2 inhibition for providing a new alternative for treating SCI.
The increasing availability of chemical probes for specific applications in chemical biology and medicinal chemistry is extensively facilitating our knowledge of biological systems. This understanding has fundamental implications in the development of new efficacious therapeutic strategies. Nowadays, successful drug discovery programs consider identification, engagement, and endogenous levels of the intended therapeutic target from the earliest preclinical stages. All these aspects are addressed with the use of chemical probes, compounds that rely on the use of a particular chemical reaction to give an answer to a specific biological question. In this review we will describe the underlying chemistry and the most recent advances experienced in the field together with their most important biomedical applications.
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