Discovery of (3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone (AZD1979), a Melanin Concentrating Hormone Receptor 1 (MCHr1) Antagonist with Favorable Physicochemical Properties

Abstract

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.

Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin‐concentrating Hormone Receptor 1 Antagonist

“…Fundamental for this assumption is central nervous system exposure in man. AZD1979 shows appropriate physicochemical properties for a central nervous system indication and excellent permeability without active efflux,9 hence supporting this assumption.…”

“…For AZD1979, it was possible to observe RO in the mouse, but there was no target‐mechanism biomarker. The RO method led to efficient compound screening, as previously reported,9 and it was used in steps 2 and 3 in the dose prediction. In general, RO data may be lacking, and one must cope with significantly reduced biomarker information (e.g., only observations of dose and EI57).…”

“…In Figure 4, the upper row reports data from a single‐dose acute experiment on lean C57BL/6 mice, whereas the bottom row reports data from an experiment in diet‐induced obese mice using the same setup as described in Johansson et al 9. but running only over 4 days.…”

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

“…A spiro oxetanylazetidinyl moiety was introduced as a building block in AZD1979, resulting in favorable physicochemical and pharmacokinetic properties compared with other four-, five-, or sixmembered ring systems investigated (Johansson et al, 2016). Similarly, the use of oxetanes was shown to improve the human microsomal stability of drug-like compounds (Burkhard et al, 2013;Scott et al, 2013).…”

Selective catalytic amination of halogenated aldehydes with calcined palladium catalysts

“…The ability to synthesize these halogenated tertiary amines on an industrial efficient way can open new possibilities for the synthesis of these pharmacophores and agrochemical intermediates. 6,7 A widely used synthesis route of these compounds involve the substitution reaction of benzylhalides by a secondary amine with the formation of an equimolar amount of ammonium salts. [8][9][10][11][12][13] The reductive amination reaction of halogenated aldehydes as a way to obtain halogenated benzylamine have also gained interest in the last decades.…”