Lead Optimization of 4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines as A_2A Adenosine Receptor Antagonists for the Treatment of Parkinson’s Disease

Abstract

4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA2A receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA2A Ki 2.3 nM, hA1 Ki 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA2A Ki 0.83 nM, hA1 Ki 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA2A Ki 0.44 nM, hA1 Ki 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation of l-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.

Adenosine A2A Receptor Antagonists in Drug Development

“…Tozadenant is clinically evaluated for PD (Phase IIB successfully completed). Another novel structure is represented by TC-G 1004 (13), a commercially available acetylamino-substituted pyrimidine derivative which shows high A 2A affinity and good selectivity (Zhang et al 2008). The benzamide 14 (Lu AA4163) was developed by Lundbeck (Mikkelsen et al 2015) and converted to a water-soluble phosphate prodrug (see below) (Figs.…”

Practical approaches to resolving reactive metabolite liabilities in early discovery

“…Replacement of the bridging nitrogen atom of an atypical antipsychotic clozapine with an oxygen atom in loxapine or with sulfur in quetiapine ( Figure 2) prevents bioactivation of the dibenzoxazepine moiety and results in a drug with improved safety profile (Uetrecht et al, 1997). Furthermore, examples where resolution of RM liability (while maintaining primary pharmacology and disposition attributes) occurred through rational medicinal chemistry design has been considered to be a success story have also been presented (Bavetsias et al, 2010;Cox et al, 2010;Crawford et al, 2012;Finlay et al, 2012;Hartz et al, 2009;Kalgutkar et al, 2010Kalgutkar et al, , 2011Kalgutkar et al, , 2013Sarabu et al, 2012;Subramanian et al, 2010;Zhang et al, 2008). For instance, fluorofelbamate was specifically designed to eliminate the RM liability of felbamate on the basis of its bioactivation mechanism ( Figure 3) (Roecklein et al, 2007).…”

Identification and Application of Antitarget Activity Hotspots to Guide Compound Optimization

“…The subsequent 3D-similarity based search resulted in the identification of the structurally related pyridine-derivative 6b with an IC 50 value of 8300 nM. [51] The alignment suggests that both pyridine moieties can be superimposed. The informative SAR pair capturing the antitarget activity hotspot in this case is represented by 6c, where the pyridine is replaced by a phenyl ring, which results in a significantly reduced CYP3A4 inhibition (IC 50 43000 nM).…”

“…Both inhibition values are obtained from the same laboratory. [51] Thus, modifying the heterocyclic moiety for CYP3A4 inhibitors lowers CYP3A4 inhibition, possibly due to disrupting the potential interaction between the aromatic nitrogen atom and the heme-iron atom. [50,52] In particular, some nitrogen-containing heterocyclic aromatic molecules, such as imidazole and pyridine derivatives, are known to inhibit cytochromes by direct coordination to the heme iron located within the substrate CYP-binding site, which is termed type-II inhibition.…”