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tfujimoto
Contributor

GW637185X, Highly BBB Penetrating COX2 Inhibitor / GSK

Usually, COX-2 inhibitors has teraryl motif structures, however, the designed structure is a biaryl skeleton and the third aryl part was connected with aliphatic linkers instead of direct bonding. The main SAR focused on the linker length and hydrophobic substitution, while fundamental phenylsulfonyl group and CF3 were fixed. COX-2 inhibitions in a human whole blood assay of optimized compounds 16, 23, 25, 26, 47 were more potent than  celecoxib, rofecoxib, and etoricoxib. The selected compounds 25 and 47 displayed excellent PK profile, and good BBB penetrating. Though a teraryl structure generally has poor solubility, this designed strategy should be applied for the improvement of solubility.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VPM5BX-5-3&_cdi=5221&_user=2645672&_o...



tfujimoto
Contributor

Piperidinyl-2-phenethylamino DPP-IV Inhibitors / Pfizer

This work is to discover a back-up to Pfizer's candidate PF-00734200 as DPP4 inhibitor. The 2,4,5-trifluorophenethylamino substructure is closely-related MK-0431, but the backbone is distinguished from beta-homophenylalanine of MK-0431. The compound 5k is a quite promising lead because this ligand efficiency is fascinating 0.5. The rapid screening synthesis with piperidine derivative, and following ADMET profiling were investigated. Advanced profiling in the rat PK/PD model and subsequent human projections identified 10gas having an acceptable human DPP-IV inhibition profile with a projected 15 mg/q.d. that was suitable for a drug development candidate.A low dose (<50 mg. q.d.) was desired to lower the risk of idiosyncratic toxicity in the clinic.

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VR2448-5-3&_cdi=5221&_user=2645672&_o...

 
tfujimoto
Contributor

Orally Bioavailable GlyT1 Inhibitors / Merck

Drug design is focused on improvement of metabolic stability of lead compound. The metabolically labile n-propyl sulfonamide could be replaced with cyclopropylmetyl sulfonamide. The cyclopropyl group has pai-property, so Merck's chemists changed it to small pai-system. The resulting imidazolyl and pyrazolyl sulfonamide have good potency and improved metabolic stability. Replacement of fluoropyridyl substitution with cyclopropylmethyl and pyperidine scaffold with cyclohexane scaffold also improved metabolic stability. 

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VR2448-2-1&_cdi=5221&_user=2645672&_o...



tfujimoto
Contributor

The influence of lead discovery strategies on the properties of drug candidates / Merck

Authors proposed to use LELP (logP / ligand efficiency) as a useful function to depict the price of ligand efficiency paid in logP. The use of a ligand-efficiency-dependent lipophilicity measure named LELP is introduced herein to help quantify progress on a desirable avenue to improved potency in settings in which potency gain is of primary importance.

http://www.nature.com/nrd/journal/v8/n3/pdf/nrd2796.pdf

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tfujimoto
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Alzheimer's disease: γ-secretase inhibitors

The first-in-class gamma-secretase inhibitor LY-450139: Semagacestat (Phase-III, Eli-Lilly), Notch inhibiting cancer treatment MK-0752 (Merck, Phase-I), modulating gamma-secretase without inferring with Notch processing E2012 (Eisai, Phase-I), Notch-sparing (0.3 nM, 193-fold selectivity) inhibitor BMS-708163 (Phase-II, BMS), long acting good brain penetrating Notch-sparing (1.3 nM, 1915-fold selectivity) inhibitor PF-3084014 (Phase-I, Pfizer), and Notch-sparing (15 nM, 15-fold selectivity) inhibitor GSI-953:Begacestat (Phase-II, Wyeth) are discussed herein.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B75D9-4TW53C2-1-1&_cdi=13033&_user=2645672&_...



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tfujimoto
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Azaindole DP1R Antagonists / Merck

DP1R antagonists,azaindole series are disclosed as backup compounds to an indole MK-0524 (now Phase-III). Merck's chemists previously optimized synthetic methods of azaindoles by thermolysis of 2-azidopyridine acrylates. They applied this method for the DP1R antagonists.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VT0X2D-4-1&_cdi=5221&_user=2645672&_o...



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tfujimoto
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GPR109a Agonists. Part 1 / Merck

A back-up of MK-0354 was studied. Optimization gave a ca. 10-fold in vitro potent compound.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4VT0X2D-D-1&_cdi=5221&_user=2645672&_o...

tfujimoto
Contributor

First-principle, structure-based prediction of hepatic metabolic clearance values in human

A first-principle, structure-based model using molecular descriptors merely was developed successfully for the prediction of human hepatic metabolic clearance, predictive performance of which was superior to the hepatocytes’ model in the study. VAMP LUMO, VAMP HOMO, cosmic torsional energy and number of Hbond acceptors were identified as the important molecular descriptors to affect CLh.

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6VKY-4T2S8K0-5-1&_cdi=6135&_user=2645672&_o...



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tfujimoto
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Medicinal chemistry approaches to DPP-IV inhibitors / Matrix

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tfujimoto
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Beyond Picomolar Affinities: Noncovalent and Covalent Binding of Drugs to Proteins / AstraZeneca

Based on Kuntz's analysis, the substrate affinity of non-covalent interactions has an upper limit as 11 pM (15 kcal / mol), and the binding energies of small molecules increase by about 1.5 kcal / mol with each non-hydrogen atom. There is a 15 kcal / mol maximum affinity of drugs and inhibitors to receptors and enzymes, and for ligands that contain more than 10 non-hydrogen atoms, the binding energy increases very little with additional atoms on the molecule. This situation could be explained rationally by Gilli's entropy-enhtalpy compensation. In contrast, binding constants for enzymes with transition states correspond to average of 22 kcal / mol and up to 38 kcal / mol, many orders of magnitude stronger than can be attributed to non-covalent factors alone. Hence, reversible or irreversible covalent binding drugs are more advantageous than non-covalent binding drug for potency.

50年以上前に量子化学、化学、生化学の先駆的研究者ライナスポーリングによって提唱された、酵素が反応の遷移状態を安定化させるという酵素反応メカニズムの中心的概念は、現在までのドラッグデザインの礎となった。酵素反応モデルは超分子化学によって体系的に研究され、シクロデキストリンのようなシンプルなホストゲストの系から酵素と基質、抗体、受容体と医薬品まで非共有結合相互作用に関わるターゲットを熱力学的に解析した結果、その結合定数は10pM (10の11乗オーダー、15 kcal / mol)で頭打ちするという事がクンツらによって示された。また、結合効率は、重原子と結合定数の傾きから理解する事ができ、1重原子につき1.5 kcal / molと算出され、最大効率化された基質は10重原子で構成された分子となる。結合エネルギーの獲得効率は元々ピーターアンドリューのアンカー理論によってその概念が打ち出されたが、ここでの数値は、その後のアンドリューホプキンスらによって体系化されたリガンド効率のガイドラインの根拠にもなっている。分子をいくら大きくしても11乗以上の閾値から活性が稼げない理由は、相互作用を獲得しようとしても、分子の自由度やフレキシビリティ、脱溶媒和エネルギーを失う事で相殺されるという、ギリらによって示された絶対不変の法則、エンタルピー/エントロピー補償則から説明される。一方で、酵素反応における遷移状態エネルギーはこれを上回る22 kcal / molから38 kcal / molであり、遷移状態アナログの阻害薬や、酵素活性中心の金属とキレート錯体を形成するタイプ、可逆的、非可逆的共有結合を形成する共有結合モディファイアは、非共有結合の補償則にはのらず、その活性値は10−1000倍強力になる場合さえある(たとえばFig. 1)。遷移状態アナログでは、アスパラギン酸プロテアーゼHIV阻害薬や、抗インフルエンザのタミフルなど、共有結合阻害でも抗生物質のβラクタム系分子など報告例は多い。主には酵素をターゲットで有効と考えられ、膜蛋白のGPCRでは適用困難と考えられるが、P2Y12拮抗薬クロピドグレルのような共有結合形成タイプの例も存在する。可逆的共有結合形成をする遷移状態ミミックの阻害薬は結合乖離速度が遅い場合があり、薬効面でも有利に作用する事が期待できる。このように共有結合モディファイアには、活性面でも薬効持続でも非共有結合タイプよりもアドバンテージがあり、アスパラギン酸プロテアーゼやカテプシンK阻害薬の成功例を見ても、リガンド探索がレアなターゲットにおいて有効に機能すると期待できる。一方で毒性リスクは常につきまとう為、リスクベネフィットバランスを考慮すれば、生活習慣病などには機能しえないが、HIVや癌はもちろん、P2Y12やカテプシンKのような急性的で命に関わるような疾患、もしくは他に有効な治療薬のないアンメットメディシナルニーズのテーマでは有効に機能しえると考えられる。

http://pubs.acs.org/doi/pdf/10.1021/jm800498e

http://www.pnas.org/content/96/18/9997.full.pdf+html?sid=55640258-8f7c-4545-8815-6317bc106595

(Kuntz's paper)

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