cancel
Showing results for 
Search instead for 
Did you mean: 
mahapatra5
New Contributor

Re: GlyT-1 Inhibitor Helps Negative Symptoms of Schizophrenia

That is fantastic news! Thanks for sharing. ~ Anirban

0 Kudos
tfujimoto
Contributor

5,5’-Disubstituted Aminohydantoins as Potent BACE1 Inhibitors / Wyeth

Wyeth's chemists previously reported cyclic amidine-based BACE-1 inhibitors. The tetrahydropyrimidine part of hit compound 1 occupied in the solvent region, so that they considered that this part could be removed. Gratifyingly, the designed aminopydantoins boosted potency, enhanced solubility, permeability, brain penetration, lowered lipophilicity and molecular weight, so that druggable parameters such as LE, LELP, LipE were improved. Extension of substitutent toward S3 (Ex. compound 20b) further improved potency while maintain LE, LELP, LipE, however, exploring the S1' region resulted in unfortunate results. Selectivity against Cat D is good but they suffered from BACE-2 selectivity.

DOI: 10.1016/j.bmcl.2009.11.052

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4XRJX4K-1-1&_cdi=5221&_user=2645672&_o...

0 Kudos
tfujimoto
Contributor

The First Synthetic FFA2 (GPR43) Agonsits (Allosteric Modulators) / Amgen

GPR43 agonists are expected for the treatment of dyslipidemia ant hother metablic disorders. The pharmacological action of GPR43 agonist would be similar to that of GPR109, but this target does not have unwanted flushing effect. The structure looks like the some kinds of GK activators, but the SAR is definitely different. For example, the stereochemistry of the eutomers are opposite. GK activator essentially needed methanesulfonyl group on the right-handed phenyl, but this group diminished GPR 43's potency.


http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4XSVR6T-4-1&_cdi=5221&_user=2645672&_o...


GK activator's paper:

J. Med. Chem., 2008, 51 (14), pp 4340–4345
DOI: 10.1021/jm8003202

http://pubs.acs.org/doi/abs/10.1021/jm8003202

0 Kudos
tfujimoto
Contributor

Metabolizing Enzyme&Transporter : Challenges in Predicting Drug Interactions / FDA

Both metabolizing enzymes and drug transporters play important roles in modulating drug absorption, distribution, metabolism and elimination. Acting alone or in concert with each other they can affect the pharmacokinetics and pharmacodynamics of a drug. This paper will present cases from recent reviews of new drug application (NDA) and literature that exemplify the role of metabolizing enzyme−transporter interplay in a drug’s disposition, and discuss challenges in predicting drug interactions. Finally, the discussion will focus on the need to leverage current knowledge to obtain more meaningful drug interaction information.

DOI: 10.1021/mp900132e

http://pubs.acs.org/doi/abs/10.1021/mp900132e

0 Kudos
tfujimoto
Contributor

(WO2009143033) MK-4305 (?), Orexin R Antagonist / Merck

Is this MK-4305 (currently developed in Phase-II Orexin antagonist)?

http://www.wipo.int/pctdb/images4/PCT-PAGES/2009/482009/09143033/09143033.pdf

0 Kudos
tfujimoto
Contributor

Lessons from 60 years of pharmaceutical innovation / Lilly

Past, current, and future of drugs... How do you manage R&D?

http://www.nature.com/nrd/journal/v8/n12/abs/nrd2961.html?lang=en

0 Kudos
tfujimoto
Contributor

WAY-258131, 5,5′-Disubstituted Aminohydantoins as Potent and Selective BACE1 Inhibitor / Wyeth

The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100× selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC50 value for BACE1 of 10 nM and exhibited comparable cellular activity (EC50 = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma Aβ40 at 8 h in a Tg2576 mouse (p < 0.001).

DOI: 10.1021/jm901414e

http://pubs.acs.org/doi/abs/10.1021/jm901414e

0 Kudos
tfujimoto
Contributor

Through the “Gatekeeper Door”: Exploiting the Active Kinase Conformation

It's nice perspective.

http://pubs.acs.org/doi/abs/10.1021/jm901443h

DOI: 10.1021/jm901443h

0 Kudos
tfujimoto
Contributor

3-oxoisoindoline-4-carboxamides as potent PARP Inhibitors / Abbott

A 7-membered intramolecular hydrogen bonding is an unexpected, but promising drug design strategy.


0 Kudos
tfujimoto
Contributor

MK-0674, an Orally Bioavailable Cathepsin K Inhibitor / Merck

MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards.

DOI: 10.1016/j.bmcl.2009.12.083

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4Y1MRPT-1-1&_cdi=5221&_user=2645672&_o...

0 Kudos