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tfujimoto
Contributor

Cyclic Acylguanidines as BACE-1 Inhibitors: Part I / Schering-Plough

Their discovered lead compounds were quite similar with Wyeth's reported compounds, however, the lead generation processes were different each other.

1) Fragment screening was investigated by NMR analysis.

2) Thioisocyanate hit was discovered. They exchanged it with alternative structure.

3) They noticed the basicity was important to interact BACE-1 enzyme.

4) Amidine seemed to be a good alternative group, however, known to bad PK profile due to too strong basicity (pKa = 12).

5) Acylguanidine should be the appropriate basicity (pKa =8.33), but the number of hydrogen bonding (5) was too high (5).

6) Hence, Schering's chemists designed cyclic acylguanidine.

7) Simple cyclic acylguanidines showed weak basicity (pKa = 4.85) because of the structure may be aromatised. So, they designed alkylated cyclic acylguanidines avoiding aromatization.

Recently, Schering opened related patents which were probably more advantageous(WO2009/131974, and WO2009/131975). These patents may include a clinical candidate.

DOI: 10.1021/jm901408p

http://pubs.acs.org/doi/abs/10.1021/jm901408p

DOI: 10.1021/jm901472u

http://pubs.acs.org/doi/abs/10.1021/jm901472u

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tfujimoto
Contributor

CP-810,123, α7 nAChR Agonist for the Treatment of Cognitive Disorders in Schizophrenia / Pfizer

They exchanged the carbamate linker with fused heterocycles.

DOI: 10.1021/jm9015075

http://pubs.acs.org/doi/abs/10.1021/jm9015075

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tfujimoto
Contributor

a Potent and Orally Bioavailable CCR2/CCR5 Dual Antagonist / Merck

The drug design was focused on reducing hERG and maintaining the potency of CCR2. Their strategy was previous obtained SAR-based design. 1) Introduction of carboxyl group reduced hERG. 2) Replacement with the aminal boosted the potency. 3) Introduction of methyl group to the piperidine core improved the potency. The resulting clinical candidate 22 showed good potency, weak hERG and various CYP enzymes inhibition, excellent PK profile. This compound exhibited very slow association and disassociation binding form. Unexpectedly, the compound 22 showed CCR5 activity.

http://pubs.acs.org/doi/pdfplus/10.1021/ml900009d

DOI: 10.1021/ml900009d

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tfujimoto
Contributor

Spirocyclic Ureas: 11β-HSD1 Inhibitors identified by Computer- Aided Drug Design / Vitae

Vitae has developed their original virtual design soft "Contour". Recently, they performed the lead generation for renin inhibitor, and following optimization afford the low molecular weight, high potency, orally available in vivo efficient compound. Their "contour" also showed good performance for 11beta-HSD1 inhibitors". They found a spiropiperidine core as a new lead. The spiropiperidine itself was not unique, but this template possessed high novelty for 11beta-HSD1( For example, Annual Reports in Medicinal Chemistry Volume 41, 2006, Pages 127-140: doi:10.1016/S0065-7743(06)41007-1 Patents-WIPO: http://www.wipo.int/pctdb/cgi/guest/search5). The representative compound showed good PK and metabolic stability (this was common problem for this target), negligible inhibition of various CYP enzymes. I guess this virtual screening soft is probably good reliable tool.
11beta HSD-1 Inhibitors :
DOI: 10.1016/j.bmcl.2009.12.082

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4Y34SR8-1-1&_cdi=5221&_user=2645672&_o...

Renin inhibitors :

DOI: 10.1016/j.bmcl.2009.11.066

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tfujimoto
Contributor

MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist / Merck

I was very surprised that CGRP R antagonists usually exhibited species-selective pharmacology. For examaple, Telcagepant exhibited approximately1500-fold higher affinity for the human and rhesus CGRP receptors as compared to the rat and dog receptors. How did they test toxicity , and estimate the safety margin? Did they investigate it by monkeys instead of mice or rats?

DOI: 10.1021/ml900016y

http://pubs.acs.org/doi/abs/10.1021/ml900016y

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tfujimoto
Contributor

Physicochemical Space for Optimum Oral Bioavailability / Pfizer

It was surprising result that underscoring the importance of considering intestinal metabolism in predicting bioavailability and dose projections in drug discovery and development settings.

DOI: 10.1021/jm901371v

http://pubs.acs.org/doi/abs/10.1021/jm901371v

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tfujimoto
Contributor

Orally Available BACE Inhibitor (Phase-II) / Ligand, Schering, Merck

Low molecular weight orally available BACE inhibitor is indeed promising, but one of the most difficult and challenging target, because asparatic protease inhibitors tends to increase molecular weight and it is difficult to obtain brain penetrant compounds. However, eventually Merck planed to develop BACE inhibitor on Phase-II. The compound was originally developed by Ligand Pharma and Schering-Plough, but now licensed in Merck.

http://www.veracast.com/webcasts/bio/ceoinvestor2010/25201265.cfm

It was the very innovative result that the compound decreased 58% beta-amyloid in CSF of human in Phase-I study (showed in slide-20).

I guess the compound should be involved in the following three patents. However, scoop of the compound seems to be quite difficult. For example, the patent WO2008103351 has over 700 pages and tremendous compounds as over 4000 !! The number of inventors as 32 implied this patent was very important.

WO2008103351

http://www.wipo.int/pctdb/en/fetch.jsp?LANG=ENG&DBSELECT=PCT&SERVER_TYPE=19-10&SORT=41287497-KEY&TYP...

WO2006138265

http://www.wipo.int/pctdb/en/fetch.jsp?LANG=ENG&DBSELECT=PCT&SERVER_TYPE=19-10&SORT=TART=1&DISP=25&F...

WO2006065277

http://www.wipo.int/pctdb/en/fetch.jsp?LANG=ENG&DBSELECT=PCT&SERVER_TYPE=19-10&SORT=41288852-KEY&TYP...

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tfujimoto
Contributor

(WO/2010/015655) CYCLOHEXYL AMIDE DERIVATIVES AND THEIR USE AS CRF-1 RECEPTOR ANTAGONISTS / Novartis

CRF antagonists usually were highly aromatised rigid, insoluble compounds. However, this Novartis chemotype was really different from those chemotypes, and maybe showed better property. I was very surprised this novel chemotype.

http://www.wipo.int/pctdb/images1/PCT-PAGES/2010/062010/10015655/10015655.pdf

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tfujimoto
Contributor

Dimebon, Alzheimer's Drug Falls Short

Dimebon's shock. Dimebon's Phase-II study seemed to show good result. Produce of a new drug for Alzheimer's disease is really difficult.

http://online.wsj.com/article/SB10001424052748703862704575099320507972894.html?mod=WSJ_latestheadlines

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tfujimoto
Contributor

Intramolecular Hydrogen Bonding in Medicinal Chemistry / Hoffmann-La Roche

Control of hydrogen bonding in medicinal chemistry is quite important, so that this paper is very helpful and these fundamental contents will be read by many medicinal chemists.

DOI: 10.1021/jm100087s

http://pubs.acs.org/doi/abs/10.1021/jm100087s

Anyway, the author was not aware of example where seven-membered ring intramolecular hydrogen bonds have been designed in medicinal chemistry. However, very recently, chemists of Abbott designed intramolecular hydrogen bonded PARP-1 inhibitor.

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 3, 1 February 2010, Pages 1023-1026

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TF9-4XY5DVP-5&_user=2645672&_coverDate=02...

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