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tfujimoto
Contributor

RO-51, Dual P2X3, P2X2/3 Antagonist / Roche

Optimization of 2-aminopyrimidine of RO-4 was reported. Discovered RO-51 showed nanomolar range dual antagonist activities, good selectivity against other subfamily and CEREP profiling. In vitro safety assessment of RO-51 (CYP, hERG, Ames, phototoxicity) was attractive, and PK profile was good. I think RO-51 is good chemical tool of this target.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VJ04MF-1-1&_cdi=5221&_user=2645672&_o...



tfujimoto
Contributor

Potent, Orally Available mGlu1 Receptor Enhancers / Hoffmann-La Roche

Fluorination of metabolic site is popular method to improve metabolic stability. To improve metabolic stability of compound 1, Roche's chemists replaced methyloxazole with trifluoromethyloxazole. The compound 14a showed good PK. mGluR is classified into class C GPCR. It is usually difficult to find orthosteric small molecule ligands with good subtype selectivity. Allosteric modulator is one of approaches to get a good subtype selectivity. Recently, there were many reports of mGluR5 positive allosteric modulators for schizophrenia. On the other hand, this paper disclosed mGluR1 positive allosteric modulator. Pharmacology of mGluR1 enhancers is very interested.

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VJBTMV-2-1&_cdi=5221&_user=2645672&_o...

 

tfujimoto
Contributor

Covalent Modifiers: An Orthogonal Approach to Drug Design / Amgen

Nonspecific covalent binding (bioactivation) may cause toxicological events. On the other hand, there are where controlled, target-specific covalent modification has proven useful. In ideal cases, the covalent modifier is typically poorly reactive with solution nucleophiles under physiological conditions, but yet upon appropriate positioning will selectively react with a nucleophile within the target protein. This review shows examples in which therapeutic targets are covalently bound by small molecule drugs. Orlistat, anti-obesity drug, has acylation mechanism with triacylglycerol lipase. Donepezil and galantamine are competitive binding with the active site serine of acetylcholinesterase. Aspirin irreversibly acylates an active site serine of prostaglandin endoperoxidase synthase. Omeprazole and ransoprazole, PPI, form disulfide bond formation. HKI-272 is an irreversible dual EGFR / HER-2 inhibitor by Michal addition. For recent noteworthy examples of Pinner reaction, cyanopyrrolidine of LAF-237 (DPP-IV inhibitor) forms a reversible covalent imidate ester adduct with the active site serine; dipeptidic nitrile of MK-0822 (Cathepsin K inhibitor) forms a reversible covalent thioimidate with the active site cysteine.

http://pubs.acs.org/doi/pdf/10.1021/jm8008597



tfujimoto
Contributor

PF-00868554 (Phase-II), Hepatitis C Virus Polymerase Inhibitor / Pfizer

The starting compound 6 had low solubility due to high crystalline form and was a potent CYP2D6 inhibitor. (0.3 micro M). CYP2D6 inhibition significantly depended on Ar1's substitution. Especially replacement of CN with OH abolished CYP2D6 inhibition, therefore CN group of compound 6 probably interacted with the CYP2D6 enzyeme possibly through hydrogen bonding. Based on crystal structure of HCV polymerase, designed ethylphenyl analogue as 16 showed good potency. Replacement of ethylphenyl with ethylpyridiyl improved water solubility, metabolic stability, and potency. Finally, Pfizer's chemists discovered PF-00868554 with an excellent profile.

http://pubs.acs.org/doi/pdf/10.1021/jm8014537



tfujimoto
Contributor

Metabolism-Dependent Genotoxicity by 5-HT2cR Agonists / Pfizer

While compound 1 was Ames positive, compound 2 was Ames negative, although both compounds has piperazine core with bioactivation risk. This paper investigated this discrepancy.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VKP3VX-2-1&_cdi=5221&_user=2645672&_o...

 
tfujimoto
Contributor

Benzothiophene MK2 Inhibitors Part 1 / Pfizer

SAR of benzothiophene MK-2 (MAPKAP-2) inhibitors was disclosed. 2-chloro,3-methylester benzothiophene 3 as an useful intermediate was prepared by the reaction of cinnamic acid 2 with thionyl chloride. Sequence of Buchwald amination of 3 with Boc-protected diamine, deprotection, and cyclization gave tricyclic target compounds. Interestingly, compound 18 bearing an aminomethyl arm shows good MK2 potency and ca. 30-fold selectivity against CDK2. This result was explained by X-ray crystallography.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VJSRWG-7-3&_cdi=5221&_user=2645672&_o...



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tfujimoto
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Benzothiophene MK2 Inhibitors Part 2 / Pfizer

To obtain selectivity against CDK2, modification of the hinge binding element in the benzothiophene class was investigated. Unique thieno-,dihydrobenzofuran structure 10 was prepared by desmethylation of 4, allylation, Claisen rearrangement, oxidation of allyl, reduction of aldehyde, mesylation, and cyclization. Pyridino-, benzothiophene 17 was prepared by cyanation and reduction of nitoroquinoline 14, Sandmyer bromination, treating methylmercaptoacetate. The optimized compounds 29 and 35 have cell potency values below 500 nM and have > 1000-fold selectivity for MK2 vs CDK2.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VJSRWG-D-1&_cdi=5221&_user=2645672&_o...



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tfujimoto
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Imidazothiazole SIRT1 Activators / Sirtris

Compound 29, potent SIRT activator, has demonstrated oral antidiabetic activity in the ob/ob mouse, DIO mouse, and Zucker fa/fa rat model. This compound should be useful as chemical tool compound.

http://pubs.acs.org/doi/pdf/10.1021/jm8012954



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tfujimoto
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PF-00734200 (Phase-IIa), DPP-IV inhibitor / Pfizer

Pfizer's DPP-IV inhibitor was disclosed. Pfizer's chemists systematically investigated multifluorinated pyrrolidines and azetidines alternative to cyano or boronic acid pyrolidines as covalent modifier. Their clinical candidate has good potency, selectivity for other isoforms, and good PK profile.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VKXC04-5-1&_cdi=5221&_user=2645672&_o...



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tfujimoto
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LXRβ Agonists / AstraZeneca

Selective LXRβ agonist is attractive target for Alzheimer's disease. The effort to optimize these hits into LXRβ selectivity is described. Hit compound 5 and reference compound 2 were docked into the active site of LXR, then lead optimization was started. Interestingly, the trifluoromethyl-methyl-hydroxy group was changed into a di-methyl-hydroxy or a di-trifluoromethylhydroxy group, then the agonist activity was lost. It can be concluded that the pKa of the 3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide group is crucial for agonist activity. Compound 20 displayed desirable pharmacokinetic profile and up regulation of ABCA1 and ABCG1 mRNA in the brain were achieved when evaluated in-vivo in mice.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VKXC04-4-3&_cdi=5221&_user=2645672&_o...

 
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