A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials.

Our objectives were to develop catalytic atom-economic processes accessing and/or incorporating versatile functionality using aryl/heteroaryl acetonitriles as substrates. We report essentially solvent-free [Cp*IrCl2]2 catalyzed redox neutral processes whereby substituted acetonitriles react with primary alcohols to deliver monosubstituted aryl/heteroaryl acetonitriles in excellent yield. We further demonstrate that such processes can be achieved by conventional or microwave heating and that bis- and tris-primary alcohols are also processed efficiently.

Microwave assisted indirect functionalization of alcohols with 1,3-dimethylbarbituric acid followed by spirocyclisation employing a sequential one-pot Ir(III)/Pd(0) catalysed process, involving the formation of three new C-C bonds, one spirocyclic ring and one di- or tri-substituted exocyclic alkene, is described.

The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na + /K + ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na + /K + ratio in vivo.

No abstract

A large-scale, robust telescoped process involving acid chloride generation and Friedel–Crafts acylation followed by hydrolysis of an ester was developed for the manufacture of a homochiral disubstituted cyclohexane. Chromatography was avoided, and instead, crystallization was employed to furnish the pure carboxylic acid. This acid was further used as a key building block for the synthesis of drug candidates via amide bond formation using various amines followed by a Suzuki coupling with a pyrazole pinacol ester. The total synthesis of one of the drug candidates on a multihundred gram scale is described.

Achieving sufficient separation of the human EtheR-a-Go-go channel has prevented many programs from reaching the clinic. For clinical programs, CNS exposure seems to have been a major challenge. Although clinical studies of MCHR1 antagonists have not been able to conclusively evaluate the concept, the body of evidence suggesting a role for MCHR1 antagonists in weight management is strong and novel chemical series still appear in the patent literature. An MCHR1 antagonist with the appropriate physical chemical properties is needed to convincingly evaluate the MCHR1 concept for obesity treatment and, as knowledge from previous programs are shared, the discovery of such a compound should be achievable.

No abstract