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