Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. Issue 1 (1st January 2019)

• Record Type: Journal Article
• Authors: Felts, Andrew S.; Bollinger, Katrina A.; Brassard, Christopher J.; Rodriguez, Alice L.; Morrison, Ryan D.; Scott Daniels, J.; Blobaum, Anna L.; Niswender, Colleen M.; Jones, Carrie K.; Jeffrey Conn, P.; Emmitte, Kyle A.; Lindsley, Craig W.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 1(2019)
• Page Start: 47
• Page End: 50
• Publication Date: 2019-01-01
• Subjects: mGlu5 -- Metabotropic glutamate receptor -- Negative allosteric modulator (NAM) -- CNS -- Structure-Activity Relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.11.017
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Identification of the minimum pharmacophore of auglurant. Development of novel saturated ethers that enhanced sp 3 character. Ether head group ablated undesired aldehyde oxidase (AO) metabolism. Matrix and iterative libraries were essential in establishing SAR. Abstract: This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp 3 character, uniform CYP450 -mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.