Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss.

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.

Small molecule and peptide therapies for chronic heart failure: a patent review (2011 - 2014).

INTRODUCTION: Chronic heart failure (CHF) is the long-term inability of the heart to meet circulatory demands under normal conditions. Effects of CHF can include increased blood volume, increased vascular resistance and compromised contractility leading to fluid retention, dyspnea and fatigue. Current standard of care for chronic systolic heart failure is directed towards managing hypoperfusion through the renin-angiotensin-aldosterone and sympathetic nervous systems. Treatment may also involve reversal of maladaptive cardiac remodeling and prevention of life-threatening arrhythmias. AREAS COVERED: This review highlights small molecule and peptidic agents for the treatment of CHF with patents published between 2011 and 2014. Targets are subdivided into inotropic agents, ventricular remodeling, diuretics and the renin-angiotensin-aldosterone system. EXPERT OPINION: CHF represents a large, unmet medical need where improved therapies are needed. The renin-angiotensin-aldosterone system pathway continues to be a major source of new therapies for CHF with new inotropic therapies emerging. Promising initial clinical results for a few approaches combined with the expectation of additional clinical results in the near future make this an exciting time in the pursuit of new treatments for CHF.