Minor structural change induced a drastic impact on gamma-secretase inhibition mechanism!! MRK-560 is an old gamma-secretase which inhibits both beta-amyloid and notch. Notch inhibiting would result in problematic toxicity. But, cyclohexane scaffold was exchanged with cyclobutane, the resulting chemotype did not inhibit Notch. Example 2 showed IC50 (Aβ40, 42) = approximately 40 nM, and 100-fold selectivity against Notch inhibition. Furthermore, Ex. 2 reduced bioactivation toxic risk and PXR activity as CYP induction potential compared to MRK-560. MRK-560 was replaced with L-881, and L-458, but Ex. 2 was replaced with L-881 but did not with L-458. These results implied normal gamma-secretase inhibitor MRK-560 and Notch sparing gamma-secretase Ex. 2 had different binding sites.
Anyway, drug synthetic strategies are fascinating.
BACE-1 inhibitor is one of the most promising targets for Alzheimer's disease, but realizing orally available BACE inhibitors is quite difficult because this target is an asparatic protease inhibitor. Recently, some reports disclosed bioavailable BACE-1 inhibitors, however, almost their compounds reduced only beta-amyloid in plasma, and did not effect beta-amyloid in brain. Therefore, BBB penetrant BACE-1 inhibitors are challenging and innovative. Eli Lilly's Late-breaking patent, WO2009134517, disclosed breakthrough compounds. Especially, compound 5 should be promising, because oral administration of a 10 mg / kg dose of the compound reduced approximately 60% beta-amyloid in CSF as well as in plasma. This compound was specific claimed at clam-7. They also described that their compounds were superior to similar but advanced Shionogi's patent compounds.
Shionogi's recent patent also showed in vivo data. For example, the compound 634 reduced approximately 80% beta-amyloid in brain of rats administered at 10 mg /kg dose.
This is a related patent.
Unfortunately, their patents were described in "Japanese character". If you want to know in details, ask me in this forum.
Deuterium is sometimes beneficial. This paper is also one of the examples.
Telaprevir (VX-950), an inhibitor of the hepatitis C virus (HCVa) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of telaprevir is its P1-(R)-diastereoisomer, VRT-394, containing an inversion at the chiral center next to the α-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of Telaprevir without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound d-telaprevir is as efficacious as telaprevir in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of d-telaprevir and telaprevir in buffered pH solutions and plasma samples, including human plasma, suggest that d-telaprevir is significantly more stable than telaprevir. Oral administration (10 mg/kg) in rats resulted in a ca. 13% increase of AUC for d-telaprevir.
Recently, Concert Pharma disclosed a patent for deuterium almorexant (now developed in phase-III) Analogues as an orexin antagonists.
Concert also reported that clinical results of a deuterium-modified paroxetine demonstrated reducing DDIs.
"Big interest in heavy drugs"
In fact, deuterium is now one of popular approaches. Deuterium may improve pharmacokinetic profile and safety. But I guess the biggest reason is patentability.
FXR and TGR5 are bile acid activated receptors. INT-747 as a bile acid like compound is a FXR agonist and currently in Phase II clinical studies. Minor modification of INT-747 gave a potent and selective TGR-5 agonist, INT-777. This compound showed GLP-1 releasing and an increase in energy expenditure in DIO mice that resulted in a significant reduction in weight gain and adiposity.
The biological screening of a collection of natural occurring triterpenoids against the G protein-coupled receptor TGR5. This work revealed that betulinic (1), oleanolic (2), and ursolic acid (3) exhibited TGR5 agonist activity in a selective manner compared to bile acids, which also activated FXR, the nuclear bile acid receptor. The most potent natural triterpenoid betulinic acid was chosen as a reference compound for an SAR study. Hemisyntheses were performed on the betulinic acid scaffold, and we focused on structural modifications of the C-3 alcohol, the C-17 carboxylic acid, and the C-20 alkene. In particular, structural variations around the C-3 position gave rise to major improvements of potency exemplified with derivatives 18 dia 2 (RG-239) and 19 dia 2. The best derivative was tested in vitro and in vivo, and its biological profile is discussed.
Previously, Pfizer's chemists reported that they failed to obtain POC of PDE9A inhibitor for diabetes.
But now, they succeeded to get POC of PDE9A in preclinical for alzheimer disease, and PF-4447943 is currently ongoing in Phase-II trial. This report disclosed how to design a key milestone compound, PF-4181366.
High throughput screening in Pfizer's chemical library discovered a potent lead compound 2, which has a good ligand efficiency and appropriate parameters for CNS drug, however, lacked solubility, metabolic stability, and selectivity especially against PDE 1c. They considered this template was good chemical feasibility because the scaffold was prepared by various hydrazine and ester derivatives. The plausible combination provided 89000 virtual compounds. They filtered that molecular weight of reagents was below 220 in order to get compact products, and they engaged amine moiety to increase the solubility, decrease the lipophilicity, and improve the metabolic stability. Indeed, the amine group was suspected for hERG, CYP2D6, and Pgp substrate, but they believed to control their parameters by tuning substituents. This filter reduced the number of compound as 3500. Further, CNS filter such as MW<430, clogP <3, TPSA<110 selected 2400 compounds. Finally, they introduced the information of x-ray crystal structure and homology model, scoring, and ranking to get 500 compounds. Designed compounds were prepared by library synthesis, and the compound 8 was obtained as potent and selective compounds. Finally, substituent of amine was investigated, thereafter PF-4181366 was identified as an orally efficient, good brain penetrant, tool compound.
It's a good news!!
I guess this compound should be included in this patent (WO2008080821).