The Role of Allylic Strain for Conformational Control in Medicinal Chemistry.

It is axiomatic in medicinal chemistry that optimization of the potency of a small molecule at a macromolecular target requires complementarity between the ligand and target. In order to minimize the conformational penalty on binding, both enthalpically and entropically, it is therefore preferred to have the ligand preorganized in the bound conformation. In this Perspective, we highlight the role of allylic strain in controlling conformational preferences. Allylic strain was originally described for carbon-based allylic systems, but the same principles apply to other types of structure with sp2 or pseudo-sp2 arrangements. These systems include benzylic (including heteroaryl methyl) positions, amides, N-aryl groups, aryl ethers, and nucleotides. We have derived torsion profiles from small molecule X-ray structures for these systems. Through multiple examples, we show how these effects have been applied in drug discovery and how they can be used prospectively to influence conformation in the design process.

Identification of novel GPR81 agonist lead series for target biology evaluation.

GPR81 is a novel drug target that is implicated in the control of glucose and lipid metabolism. The lack of potent GPR81 modulators suitable for in vivo studies has limited the pharmacological characterization of this lactate sensing receptor. We performed a high throughput screen (HTS) and identified a GPR81 agonist chemical series containing a central acyl urea scaffold linker. During SAR exploration two additional new series were evolved, one containing cyclic acyl urea bioisosteres and another a central amide bond. These three series provide different selectivity and physicochemical properties suitable for in-vivo studies.

Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection.

The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators ( S)-1 and ( S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of ( S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na+/K+ ratio in vivo.

Selective Synthesis of Spirooxindoles by an Intramolecular Heck-Mizoroki Reaction.

We report a highly diastereoselective synthesis of cyclopentene-spirooxindole derivatives via an intramolecular Heck-Mizoroki reaction using aryl bromides as precursors. The reactions were performed under dry conditions or in a DMF-water system. This protocol can be useful to introduce several functionalities to the aromatic nucleus of the spirooxindoles. DFT calculations were performed to rationalize the high antiselectivity. A functionalized spiroproduct was transformed into a cyclic amino acid derivative.

Regio- and Stereoselective Synthesis of Functionalized Cyclopentene Derivatives via Mizoroki-Heck Reactions.

Pd(0)-catalyzed Mizoroki-Heck alkenylations and arylations of protected aminocyclopentenes, prepared in a few steps from Vince lactam, afforded functionalized cyclopentenes in high yields and stereoselectivities. DFT calculations were performed to rationalize the high diastereoselectivities. Functionalized cyclopentene products were transformed into valuable chiral building blocks, such as cyclic γ-amino acids and carbocyclic nucleoside precursors.

Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability.

The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.

Unexpected Retroaldol-Aldol Reaction during O-Alkylation of Hydroxylated Vince Lactam Derivatives.

The unexpected retroaldol-aldol reaction during O-alkylation of a ß-hydroxy lactam was found to be highly dependent on the temperature and shows a remarkable solvent effect. In DMF, O-alkylation is faster than retroaldol-aldol rearrangement giving exclusively products with retention of configuration. In THF, O-alkylation is slower than rearrangement, giving selectively products with inversion of stereochemistry. In DMSO, a retroaldol reaction followed by fast intramolecular proton transfer occurs to give the ring-opened aldehyde.

Synthesis of potential thrombin inhibitors. Incorporation of tartaric acid templates as P2 proline mimetics.

With the objective to prepare novel non-peptidic thrombin inhibitors, bioisosteres of the inhibitory tripeptide D-Phe-Pro-Arg chain have been examined. Thus, the P1 Arg was replaced with p-amidinobenzylamine, an elongated homologue of the same and with 2,5-dichloro benzylamine. The P2-P3, D-Phe-Pro, was replaced with a novel tartaric acid template coupled to a series of readily available, mainly lipophilic, amines. Some of these compounds exhibit promising thrombin inhibition activity in vitro, IC(50 ) approximately 5.9 microM.

Synthesis of [4,5-Bis(hydroxymethyl)-1,3-dioxolan-2-yl]nucleosides as Potential Inhibitors of HIV.

The synthesis of 1,3-dioxolan-2-ylnucleosides and related chemistry is described. We have shown that 2-methoxy-1,3-dioxolane (6) reacts with silylated thymine and trimethylsilyl triflate to give the acyclic formate ester 1-[2-(formyloxy)ethyl]thymine (8) rather than 1-(1,3-dioxolan-2-yl)thymine (7). A tentative mechanism which could explain this result is discussed. On the other hand, 2-methoxy-1,3-dioxolane 13c reacts with silylated bases to give [4,5-bis(hydroxymethyl)-1,3-dioxolan-2-yl]nucleosides, thus representing the first examples of this novel class of compounds. The nature of the nucleobase and the hydroxyl protecting groups was found to have great influence on the reaction and on the stability of the nucleosides. Compounds 16 and 18 were found to be inactive when tested for anti HIV-1 activity in vitro.

Synthesis of [4,5-Bis(hydroxymethyl)-1,3-oxathiolan-2-yl]nucleosides as Potential Inhibitors of HIV via Stereospecific Base-Induced Rearrangement of a 2,3-Epoxy Thioacetate(1).

The synthesis of [4,5-bis(hydroxymethyl)-1,3-oxathiolan-2-yl]nucleosides is described. 2,3-Epoxy alcohol 10 was converted in one pot into thioacetate 11. Treatment of 11 under mild alkaline conditions gave thiirane 12 with inversion of configuration at C-2. We also found that thioacetate 11 rearranges into thiirane 14 under mild acidic conditions. This rearrangement reaction was shown by independent synthesis to proceed with net retention of configuration at C-2. We have proposed a tentative mechanism which may explain the results obtained. Opening of thiiranes 12 and 14 followed by deprotection gave (2R,3R)-2-thiothreitol (23) and (2S,3R)-2-thioerythritol (25), respectively. Regioselective silylation of the primary hydroxyl groups of 23 followed by treatment with trimethyl orthoformate gave 2-methoxy-1,3-oxathiolanes 26 and 27. Condensation with silylated bases followed by deprotection and separation of the anomers gave the oxathiolanylnucleosides. Compounds 29-31, 34, and 35 were found to be inactive when tested for inhibition of HIV-1 activity in vitro.

Synthesis of [4,5-Bis(hydroxymethyl)-1,3-dithiolan-2-yl]nucleosides as Potential Inhibitors of HIV(1).

The synthesis of [4,5-bis(hydroxymethyl)-1,3-dithiolan-2-yl]nucleosides is described. (2S,3S)-1,2:3,4-Diepoxybutane (13) was reacted with potassium thiocyanate to give (2R,3R)-1,2:3,4-diepithiobutane (14). Thiiranering opening with acetate followed by deacetylation gave (2R,3R)-2,3-dithiothreitol (19) which was silylated and treated with trimethyl orthoformate to give the 2-methoxy-1,3-dithiolane 20. Condensation of 20 with silylated thymine, uracil, N(4)-benzoylcytosine and 6-chloropurine using a modified Vorbrüggen procedure, followed by deprotection, gave the nucleoside analogues. Compounds 26, 28, and 30 were found to be inactive when tested for anti-HIV activity in vitro.