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    • In three independent groups identified GPR

    2022-01-06

    In 2003, three independent groups identified GPR109A (HM74A) and GPR109B (HM74), two GPCRs, as the receptors for niacin., , GPR109A, which is present in all species, is a high affinity receptor for niacin., GPR109B, which is only present in human and chimpanzee, is a low affinity receptor for niacin., The lack of this ortholog in rodents suggests that GPR109A is sufficient for the antilipolytic activity of niacin in vivo., However, Phenacetin of the GPR109A-receptor in mice showed that this receptor can be responsible for both effects of niacin: lipid lowering as well as prostaglandin-mediated transient skin vasodilation. Several approaches to dissect the desired dyslipidemic effects from the undesired flushing effect are under discussion: (i) avoid high values (e.g., like with immediate release niacin), and strive for low / ratios (e.g., slow release niacin) assuming that drives the flushing; (ii) combine niacin or a novel GPR109A agonist with aspirin or a prostaglandin D2 inhibitor; (iii) use positive allosteric agonists; (iv) develop partial GPR109A agonists. Supported by the comparison of immediate release niacin versus sustained release niacin, we hypothesized that a pharmacokinetic profile which is characterized by a low / ratio, a very low volume of distribution and a very low clearance is essential to achieve a separation between desired and side effect. Immediate release niacin (high /) causes flushing in >90% of all patients whereas sustained release also called ‘no flush’ niacin (low /) avoids flushing but leads to severe liver toxicity. Since this liver toxicity is linked to a niacin specific metabolite we were confident to overcome this issue with a structurally different GPR109A agonist. To probe the PK hypothesis a chemistry program based on the high throughput screening hit was initiated. The optimization of the in vitro activity of these pyrido pyrimidinones on GPR109A will be described in this Letter. Receptor-based modeling driven mutational studies supported the medicinal chemistry efforts. Niacin and pyrido pyrimidinone were docked into a 3D receptor pharmacophore model of the GPR109A transmembrane binding pocket (). The binding mode hypothesis of niacin is in agreement with the work of Tunaru et al. and in-house site-directed mutagenesis studies. It proposes an interaction of the carboxyl group of nicotinic acid with R111 at TM3 and a hydrogen bond between the nitrogen of the pyridine ring and the hydroxyl group of the at EC2. The pyridine ring is embedded between TM2/EC1 and TM7 (Y284). The additional critical determinants, F276 and amino acids in the EC1 (N86, W91), of the niacin binding pocket are in close proximity to the hypothesized binding mode of niacin, but are not shown due to reasons of clarity. In addition, a possible binding mode for pyrido pyrimidinone is presented. The nitrogens of the pyridine and pyrimidinone ring mimic the carboxyl group of the nicotinic acid interacting with R111 at TM3 and the carbonyl group of the pyrimidinone forms a hydrogen bond with the hydroxyl group of the at EC2. The trifluoro substituent points towards the binding pocket arranged by TM5 and TM6 demonstrates the possibility to extend this exit vector. HTS hit already has interesting binding affinities to the human and rat receptor as well as good functional activity (). Unfortunately, clearance determined in vitro from rat liver microsome incubations was high. This translated also into a high clearance in vivo which was accompanied by a short plasma half-life in rat after iv dosing leading overall to a high / value. Therefore, further in vivo profiling was prohibited and an in vitro optimization program was initiated. As expected from the proposed binding mode derived from the mutational studies, the pyrido pyrimidinone scaffold is essential for activity. Replacement of any of the nitrogen atoms by a carbon atom or alkylation of the pyrimidinone-NH rendered the scaffold significantly less active or even inactive (data not shown). Moreover, the trifluoro-methyl group could not be replaced with small alkyl, acyl, aryl, alkoxy, and alkylamino groups without substantial loss of activity. Based on the modeling hypothesis, the possibility to extend this exit vector was probed and substituents containing a phenyl group attached to a simple alkyl-chain linker were identified as suitable replacements for the trifluoro-methyl group ().