¹ Lowering Lipophilicity by Adding Carbon: One-Carbon Bridges of Morpholines and Piperazines

J. Med. Chem. 2018, 61, 19, 8934-8943

Authors report that it is possible to lower lipophilicity of 6-membered rings such as piperazine, piperidine an morpholine without introducing additional heteroatoms. In particular, they describe that bridging piperazine across the ring with one-carbon tether leads to a counterintuitive reduction in lipophilicity. This modification lowered the measured log^D7.4of the bridged molecules by as much as −0.8 relative to their unbridged counterparts.

In the series of N-Ac piperazine IRAK4 inhibitors 1a-c, the two symmetrical one-carbon bridges were found to only slightly increase basicity (ΔpKa = +0.3) and showed a beneficial impact on hepatic metabolism stability and hERG inhibition.

This observation potentially provides a useful tactic to modulate the physicochemical properties of piperazine derivatives, especially in cases where issues are observed with metabolism, hERG inhibition, or other detrimental properties correlated with lipophilicity.

² Synthesis of Azaspirocycles and their Evaluation in Drug Discovery

Angew. Chem. Int. Ed. 2010, 49, 3524

Although metabolic susceptibility is dependent on the structural context, and thus cannot generally be attributed on a given structural subunit of interest, it was found that most spiro[3.3]heptane derivatives were oxidatively degraded at lower rates than the six-membered monocyclic analogues in both human and mouse liver microsomes.
As case study, the homospiropiperazine and homospiromorpholine analogs of the antibacterial compound ciprofloxacin were prepared and evaluated.

The homospiropiperazine derivative 1 displayed 4-8-fold weaker inhibition than ciprofloxacin, however the homospiromorpholine analog 2 displayed comparable activity.

Moreover, metabolic studies revealed spiroisosters 1 and 2 to have high stabilities, with no observable metabolism in human microsomal assays whereas ciprofloxacin trifluoroacetate shows slight metabolic degradation. Likewise, 1 was as stable as ciprofloxacin in a human hepatocyte assay, whereas the homospiromorpholine analogue 2 remained essentially unaffected under the same whole-cell assay conditions.

³ Highly Selective Dopamine D3 Receptor Antagonists with Arylated Diazaspiro Alkane Cores

J. Med. Chem. 2017, 60, 9905-9910

The dopamine D3 receptor (D3R) is a protein of interest for various neurological and neuropsychiatric disorders including schizophrenia, Parkinson’s disease, dementia, anxiety and depression. However, the similarities shared between the near-identical binding site residues of the D3R and the dopamine D2 receptor (D2R) receptors have made the development of a FDA approved D3R selective therapeutic quite challenging.

Encouraged by previous successful reports, the authors prepared a new class of D3R scaffolds using diazaspiro alkanes as modified amino cores. They noticed an increase in D3R potency and D3R/D2R selectivity by replacing the piperazine ring with bulky diazaspiro cores.

Actually, as spirodiamines provide spatial modifications that are non accessible to piperazine, unique interactions can be generated in the D3R binding pocket leading to an improvement of the D3R/D2R selectivity.

⁴ Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity

J. Med. Chem. 2018, 61, 5367-5379

In the present study, researchers investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of Olaparib, an FDA approved poly(ADP-ribose) polymerase inhibitor (PARPi). Synthesized analogues were screened for PARP-1 affinity, enzyme specificity, catalytic inhibition, DNA damage, and cytotoxicity.

This work led to the identification of the 2,6-diazaspiro[3.3]heptane derivative 2 which did not induce DNA damage at similar drug concentrations as Olaparib.Indeed, western blot and cell microscopy analysis demonstrated that 2 inhibits PARP-1 activity but does not induce the marker of DNA damage γ-H2AX foci equally, demonstrating that it not causes DNA double-strand breaks at micromolar concentrations. Moreover, off-target interactions with other PARPs were explored with Olaparib and 2. Compared to Olaparib, 2 demonstrated less enzymatic inhibition with most other PARPs, further highlighting it as the best-in-class compound.

Finally, this study provided further evidence that high affinity PARPi’s can be developed without DNA damaging properties offering potential new drugs for treating inflammatory related diseases.

⁵Heteroaryl-substituted spirocyclic diamine urea modulators of fatty acid amide hydrolase

WO2010141817

The present invention specifically relates to heteroaryl-substituted spirocyclic diamine urea compounds (I), which are useful as FAAH inhibitors. Such compounds may be used for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, energy metabolism disorders, and movement disorders (e.g., multiple sclerosis).

The patent covers a large set of spirodiamines derivatives with modulated N-N distance such as:

The switch from piperazine to substituted, fused, bridged or spiro bicyclic derivatives gives access to a set of constrained diamines with modulated N-N distance. It offers the opportunity to fine tune the molecule geometry and confer some target specific benefits.

In particularly, the conformational restriction can potentially be used to improve selectivity and/or increase potency via subtly changing the shape of the moiety.