Considering solubility, permeability, metabolic clearance, oral bioavailability, distribution, preclinical safety margin for animal toxicity test, hERG inhibition, CYP inhibition, and phospholipidosis, druggable compounds are required for appropriate lipophilicity as 1<log P or log D <3.
Bissantz C, Kuhn B, Stahl M. A Medicinal Chemist's Guide to Molecular Interactions. Journal of medicinal chemistry. 2010.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20345171.
This is nice review of fundamental science for molecular interactions related with medicinal chemistry. Especially, I was impressed with sulfonyl group's property. The sulfonyl group make lipophilicity of a compound reduced. In this paper, the sulfonyl group was favorite in hydrophobic pocket, so that, this group has good chance to reduce lipophilicity and maintain the potency.
Perola E. An Analysis of the Binding Efficiencies of Drugs and Their Leads in Successful Drug Discovery Programs. Journal of medicinal chemistry. 2010.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20235539
This report implies ligand efficiency is not always a good index for selection of a lead compound. I agree with this result. I think ligand efficiency is not criteria, but alert. I suppose a lead compound with low ligand efficiency is not always poor starting point. Low ligand efficiency means that we should optimize the compound without increasing molecular weight. The analysis of this report is quite interesting because many drugs were started from low ligand efficient lead compounds.
The issue of final optimization is overcoming hERG inhibition and good CNS penetration. Particular CNS penetration is estimated by Roche's automated SAR analysis by ROSASA(Fischer, H.; Kansy, M. Automated Generation of Multi-Dimensional Structure Activity and Structure Property Relationships. PCT Int. Appl. US 2007027632, 2007.). By this method, CNS penetration depends on only PSA and clogP. This method assisted to discover RG-1678.
GPR40 was originally orphan GPCR, which was consequently found and deporphanized almost coincidentally by GSK and Takeda. Takeda's persistent effort achieved a clinical candidate TAK-875. This report disclosed the structure.
Dr. Margaret A. Hamburg (the commissioner of the FDA) and Francis S. Collins (the director of the NIH) describes the progress and perspectives of "personalized medicine". FDA and NIH want to accelerate and support this science, and construct the system.
Orexin receptor antagonist is quite fascinating target for treatment of insomnia with good efficacy and negligible side-effect. This paper disclosed MK-4305, now developed in Phase-III. The main issue was to improve PK profile and reduce toxic potential by bioactivation. The first trial was modification of metabolically susceptible diazepam. Next, quinazoline was replaced with benzoxazole to reduce bioacativation. The resulting MK-4305 showed quite promising profile.
Tyagarajan S, Chakravarty PK, Zhou B, et al. Substituted Biaryl Oxazoles, Imidazoles and Thiazoles as Sodium Channel blockers. Bioorganic & Medicinal Chemistry Letters. 2010.
Available at: http://linkinghub.elsevier.com/retrieve/pii/S0960894X10010206.
I mentioned two interesting isosteric transformation from V102862. One of them is exchange arylether with ortho-phenyl. This transformation looks like tricky, however, this isosterism between bent type biarylether and linear type biphenyl is somewhat valuable. The ohter replacement is two types of constraint of semicarbazone: thiazolidione and azole. Those replacements maintain the position of hydrogen bonding. Semicarbazone is probablely chemically unstable and has chemical toxicity. This isosteric change is also valuable.
Abbenante G, Becker B, Blanc S, et al. Biological Diversity from a Structurally Diverse Library: Systematically Scanning Conformational Space Using a Pyranose Scaffold â€ . Journal of Medicinal Chemistry. 2010:100722143554041.
Available at: http://pubs.acs.org/doi/abs/10.1021/jm1002777.
Classically, R.Hirschmann, K. C. Nicolaou and A. B. Smith et al showed D-glucose had fascinating potential for bioactive scaffold such as beta turn mimetics of somatostatin's phenylalanine, triptophane, and lysine. This classical scaffold comes again. In this report, the authors investigated various conformers of pyranose, and following thier SAR of SSTR2-5 and MCH.
Wood MR, Schirripa KM, Kim JJ, et al. Novel CGRP Receptor Antagonists from Central Amide Replacements Causing a Reversal of Preferred Chirality. Bioorganic & Medicinal Chemistry Letters. 2010.
If you confront an event that SAR continuity on one chemotype is sudenly lost and whose rationale is diffilucult to explain, such a "missing-link" situation may be a prognostic to a new chemotype with critical different SAR. I think that this report is one of examples such as "chemotype-missing-link". In this report, the initial approach is isosteric replacement of anilide with quinoline 2, however, which is detrimental to the potency. While the enantiomeric quinoline isomer (S)-2 is almost superimposed with anilide 1, the branched chain of other isomer (R)-2 is mismatched with anilide 1. Redesign from (R)-2 afforded potent comound 4 with (R) chirality. Through this optimization, preferred chirality is reversed by mismatch of the position of nitrogen. This "missing-link" is a prognostic to a new chemotype. In fact, following SAR of the quinoline is different from previous anilide SAR. Different SAR give a oppotunity to obtain a different structural feature and property. "Chemotype missing-link" is good oppotunity for new chemotype generation from old one, however, it is difficult to discover it unless researcher has a good insight for unexpcted observation, followed by good idea "linking" with old and new chemotype.