Disclosed are small molecules against cereblon to enhance effector T cell function. Methodos of making thes molecules and methods of using them to treat various disease states are also disclosed.

In alternative embodiments, provided are peptides and peptide-comprising compositions, including products of manufacture and kits, and methods, for modulating myosin subfragment-2 coiled coil stability. In alternative embodiments, a peptide modulator of myosin subfragment-2 coiled coil stability as provided herein is administered to an individual in need thereof for: increasing exercise tolerance in a subject with heart failure; reducing hospitalization in a subject with heart failure; improving quality of life in a subject with heart failure; decreasing morbidity in a subject with heart failure; decreasing mortality in a subject with heart failure; modulating skeletal muscle activity for purposes of impacting patient weight; and/or, modulating skeletal muscle activity for purposes of ameliorating consequences of skeletal muscle diseases such as sarcopenia, muscular dystrophies, muscle cramps, and nemaline myopathies.

In alternative embodiments, provided are peptides and peptide-comprising compositions, including products of manufacture and kits, and methods, for modulating myosin subfragment-2 coiled coil stability. In alternative embodiments, a peptide modulator of myosin subfragment-2 coiled coil stability as provided herein is administered to an individual in need thereof for: increasing exercise tolerance in a subject with heart failure; reducing hospitalization in a subject with heart failure; improving quality of life in a subject with heart failure; decreasing morbidity in a subject with heart failure; decreasing mortality in a subject with heart failure; modulating skeletal muscle activity for purposes of impacting patient weight; and/or, modulating skeletal muscle activity for purposes of ameliorating consequences of skeletal muscle diseases such as sarcopenia, muscular dystrophies, muscle cramps, and nemaline myopathies.

The present invention relates to compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the beta-3 adrenergic receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a beta-3 adrenergic receptor-mediated disorder, such as, heart failure; cardiac performance in heart failure; mortality, reinfarction, and/or hospitalization in connection with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; cardiovascular mortality following myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; class II heart failure using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; class IV heart failure using the New York Heart Association (NYHA) classification system; LVEF<40% by radionuclide ventriculography; LVEF≤35% by echocardiography or ventricular contrast angiography; and conditions related thereto.

The present invention relates to compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the beta-3 adrenergic receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a beta-3 adrenergic receptor-mediated disorder, such as, heart failure; cardiac performance in heart failure; mortality, reinfarction, and/or hospitalization in connection with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; cardiovascular mortality following myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; class II heart failure using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; class IV heart failure using the New York Heart Association (NYHA) classification system; LVEF<40% by radionuclide ventriculography; LVEF≤35% by echocardiography or ventricular contrast angiography; and conditions related thereto.

The invention relates to new bicyclic heterocycle compounds, to pharmaceutical compositions comprising the compounds and to the use of the compounds in the treatment of diseases, e.g. cancer.

Long-acting agonistic analogs for CLR/RAMP receptors are provided that have an extended half-live in vivo. The agonists are delivered to an individual at a dose sufficient to reduce hypertension and ischemic injury, and to reduce cardiotoxicity associated with chemotherapeutic agents.

Long-acting agonistic analogs for CLR/RAMP receptors are provided that have an extended half-live in vivo. The agonists are delivered to an individual at a dose sufficient to reduce hypertension and ischemic injury, and to reduce cardiotoxicity associated with chemotherapeutic agents.

The present disclosure relates to novel sulfonylurea and sulfonyl thiourea compounds and related compounds and their use in treating a disease or condition responsive to modulation of cytokines such as IL-1β and IL-18, modulation of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.

According to the invention there is provided a compound of formula A1 which may be useful in the treatment of a condition or disorder ameliorated by the inhibition of the A.sub.1-A.sub.2b or, particularly, the A.sub.2a receptor wherein the compound of formula A1 has the structure, wherein, A represents Cy.sup.1 or Het.sup.A; Cy.sup.1 represents a 5- to 14-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one, two or three rings, which Cy.sup.1 group is optionally substituted by one or more R.sup.4a substituents; Het.sup.A represents a 5- to 14-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more hetermatoms selected from O, S and N, which heterocyclic group may comprise one, two or three rings and which HetA group is optionally substituted by one or more R4b substituents; B represents a Cy.sup.2 or Het.sup.B; Cy.sup.2 represents a 3- to 10-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one or two rings, which Cy.sup.2 group is optionally substituted by one or more R.sup.4c substituents; Het.sup.B represents a 3- to 10-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one or two rings and which Het.sup.B group is optionally substituted by one or more R.sup.4d substituents.

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