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These organic compounds are effective in treating metabolic, cardiovascular and renal diseases. Cardiovascular diseases are the leading cause of death globally. Hypertension, a common cardiac disease, is the primary risk factor for heart failure, myocardial infarction, sudden cardiac death, chronic kidney disease, stroke, and dementia. Therefore, lowering blood pressure is essential to mitigate the risk of developing severe cardiac disease and to improve outcomes.
The particulate guanylyl cyclase receptor A (pGC-A) is the molecular target of the cardiac hormones atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). The binding of ANP or BNP to pGC-A produces cyclic 3’,5’-guanosine monophosphate (cGMP), involved in physiological functions such as regulation of blood pressure and endocrine and renal functions, as well as cardiovascular protection from obesity. Previous studies have shown that individuals expressing elevated levels of ANP or BNP are at a lower risk for developing hypertension or type II diabetes, respectively, signifying the protective role of pGC-A. Additionally, administration of BNP can reverse cardiac hypertrophy and improve myocardial function in patients. However, although activation of the pGC-A/cGMP pathway depicts an attractive pharmacological target for metabolic, cardiovascular and renal, the rapid clearance of ANP and BNP poses an obstacle to efficiently leveraging its protective functions.
Researchers at the University of Florida have discovered a group of halobenzo[d]thiazole compounds, effective in treating metabolic, cardiovascular and renal diseases. This class of organic compounds increases the responsiveness of the particulate guanylyl cyclase receptor A(pGC-A) to the endogenous ligands ANP and BNP, leading to enhancement of pGC-A activity and increased production of cyclic guanosine monophosphate(cGMP).
Activation of the endogenous pGC-A/cGMP pathway to restore or augment natural levels and treat metabolic disease, cardiovascular disease, and renal disease
These halobenzo[d]thiazole compounds can effectively treat metabolic, cardiovascular and renal diseases by enhancing the particulate guanylyl cyclase receptor A (pGC-A). pGC-A is the molecular target of the cardiac hormones atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), functioning via the production of cyclic 3’,5’-guanosine monophosphate (cGMP). Production of cGMP after binding the ANP and BNP to pGC-A, results in the regulation of blood pressure, obesity, and cancer, as well as renoprotective and cardioprotective actions. These halobenzo[d]thiazole increase pGC-A responsiveness to ANP and BNP in a positive allosteric fashion, activating the pGC-A/cGMP pathway and increasing cGMP production.
These thiadiazine-based small molecules promote wound healing and tissue repair in diabetic patients. Diabetes incidence has reached epidemic proportions in the United States and globally, and impaired diabetic wound healing is a growing problem. In severe cases, it triggers a chronic inflammatory state, leading to the development of vascular disease and impaired wound healing. Lower extremity ulcers are the leading cause of hospitalizations and amputations among diabetic patients, underscoring the critical need for therapeutics effectively promoting wound healing. The development of such therapeutics has the potential to enhance patient outcomes and reduce healthcare expenditures, estimated at approximately $1.5 billion annually.
Diabetic wounds lack the expression of SDF-1a (stromal-derived factor-1a), which is essential for controlled wound healing. SDF-1a canonically binds to CXC chemokine receptor type 4 (CXCR4), serving as a signal to recruit hematopoietic cells to the location of tissue injury and promote tissue repair. Reduced expression of SDF-1a in diabetic wounds signifies its contribution to wound healing and depicts the CXCR4 receptor as a target for diabetic wound therapeutic development.
Researchers at the University of Florida have synthesized small molecule CXCR4 agonists to promote wound healing and tissue repair in diabetic patients. By binding to and activating the CXCR4 receptor, the agonists trigger hematopoietic cell recruitment to wound sites and necessary protein production to stimulate tissue repair.
Binds to and activates CXCR4 to recruit hematopoietic cells to wound sites and promote diabetic wound healing
University of Florida researchers have formulated small molecule agonists of the CXC chemokine receptor type 4 (CXCR4) to improve wound healing in diabetic patients by recruiting hematopoietic cells to wound sites. The CXC chemokine SDF-1a is a vital regulator of the recruitment of hematopoietic cells to injury locations to promote tissue repair through binding and activating the CXR4 receptor. However, diabetic wounds show decreased expression of SDF-1a, leading to impaired wound healing. These thiadiazine-based small molecules bind to and activate the CXCR4 receptor in an allosteric manner to recapitulate flawed recruitment of hematopoietic cells and collagen I production in wound sites and angiogenesis. The allosteric binding of these compounds to CXCR4 leads to no competition with the endogenous ligand SDF-1a, enabling synergistic effects. This system has shown significant improvements in the rate of wound closure in mouse models of diabetic wounds, decreasing wound healing time and potentially increasing patient outcomes.