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tfujimoto
Contributor

Hydroisoindoline-Based NK1R Antagonists / Merck

An aprepitant (compound 1) is now the sole marketed NK1R drug. Merck's chemists designed novel hydroisoindoline-based NK1R antagonists by merging an aprepitant with a vinylogous amide 2. It was very impressed that five chiral stereocenters were manipulated by Diels-Alder reaction and the ether formation with the trichloroacetimidate derivative.

NK1受容体拮抗薬のドラッグデザイン。既に発売済みのアプレピタントとバックアップ化合物を融合させたヒドロイソインドール系化合物をデザイン。5つの不斉炭素が複雑に絡み合った化合物を、ディールズアルダー反応を鍵反応として4置換シクロヘキサンを構築、組み上げて行く様は流石。

http://pubs.acs.org/doi/pdf/10.1021/jm8016514

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tfujimoto
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α1A Adrenoceptor Partial Agonists / Pfizer

Pfizer's chemists have already discovered a tetrahydronaphtalene 1 and dihydroindane 2. Alpha 1A partial agonists have a structural motif of simple templates linking an aryl ring to an imidazole. Further drug design is scaffold morphing such as benzo-shifting (compound 4), benzo-cracking (compound 5), nitrogen shuffle (compound 7), and ring-shrinking or -expanding (compounds 6-7). The resulting templates 6 and 7 were particulary interesting as they lacked the N-H of most imidazole or imidazoline alpha-agonists. The good profile templates 5 and 6 were optimized substitution of a phenyl ring to give a nitrile compound 28, which had acceptable potency, good selectivity, excellent matabolic stability, and passive membrance permeability, negligible hERG channel inhibition, good profile of MDR.
ファイザーではα1A部分作動薬としてテトラヒドロナフタレン1及びジヒドロインダン2を見出しており、これを起点に新規ケモタイプの創出を検討している。α1A部分作動薬は、イミダゾールとベンゼン環のファーマコフォアを適切な距離に配置する必要がある。その為に、スッキャーホールドモーフィング、すなわちベンゼン環の移動(4)、ベンゾクラッキング(5)、窒素シャッフル(7)、環拡大ー縮小(6)したテンプレートをデザインして合成した。αアドレノレセプター作動薬にはイミダゾールのNHがほぼ必須であるにも関わらず、化合物6、7のようにNHがアルキル化されたものでも活性があるのは極めて興味深い結果である。活性面で有望なテンプレート5、6を最適化し、テンプレート6でニトリル基を有する28は、良好な活性と選択性、優れた代謝安定性、PAMPA膜透過性、MDRで問題がなく、hERG阻害作用は弱く、優れたADMEプロファイルと中枢移行性を示した。
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4W15KPP-1-1&_cdi=5221&_user=2645672&_o...

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tfujimoto
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Conformational Analysis of Diazepane Orexin R Antagonists / Merck

NMR spectroscopy, X-ray crystallography, and molecular modeling studies indicate that N,N-disubstituted-1,4-diazepane orexin receptor antagonists exist in an unexpected low-energy conformation that is characterized by an intramolecular π-stacking interaction and a twist-boat ring conformation. It is interesting that an exo-cyclic amide bond might trigger a change in ring conformation from chair to boat. Synthesis and evaluation of a macrocycle that enforces a similar conformation suggest that this geometry mimics the bioactive conformation. The key synthetic steps of this fascinating macrocyclic structure are a copper-catalyzed C-N cross-coupling, an allylation by Stille coupling, a Negishi coupling with pentenylzinc bromide, and a RCM with Zhan-1B catalyst.

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4W2NDNJ-3-1&_cdi=5221&_user=2645672&_o...

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tfujimoto
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Mechanistic Insights into COX Irreversible Inactivation by Aspirin

A mechanistic hypothesis for the acetylation of cyclooxygenase (COX) by aspirin is proposed on the basis of a QM/MM study. This mechanism is consistent with previous experimental findings by other investigators. Ser 530 appears to be acetylated under intramolecular general base catalysis provided by the carboxylate moiety of aspirin, while Tyr 385 plays a crucial role in orienting and polarizing the acetyl group.

抗炎症薬COX阻害薬で最古にして唯一の共有結合モディフィア、アスピリンの酵素との結合メカニズムをインシリコで解析。チロシン385がアセチル基の配向と分極に寄与し、セリン530がアセチル化されて不活性化するとしている。

http://www3.interscience.wiley.com/user/accessdenied?ID=122265252&Act=2138&Code=4719&Page=/cgi-bin/f...

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tfujimoto
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Aminoheterocycles as Novel BACE-1 Inhibitors, Part 1 / Merck

The initial hit comound 1 without a transition-state isoster has a week potency (IC50 = 217 maicro M), but its compact size represented an alluring ligand efficiency value of 0.3. Lead optimizatin gave the compound 7 (IC50 = 3.2 micro M), which showed unique binding mode to the enzyme: 1) Interaction directly with the catalytic dyad through a bidentate interaction; 2)The methoxy phenyl portion was observed to be involved in an extended face-to-point-to face pai-stack with Phe-108 and Phe-109; 3) The inhibitor bound in a 'flap-open' enzyme conformation.

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4W3HX4M-F-1&_cdi=5221&_user=2645672&_o...


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tfujimoto
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3,5-Disubstituted Benzamides as GK Activators / Banyu

An initial lead compound 2a had high lipophilicity and and poor solubility. Banyu's chemists examined various hydrophilic substitution, and then they discovered a compound 6g bearing an asymmetric isopropyl alcohol branch. The key breakthrough is successful to uncouple the relationship the relationship between potency and hydrophobic.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF8-4W4TXWB-2-3&_cdi=5220&_user=2645672&_o...

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tfujimoto
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GK Activators: a Metabolic Liability of the 4-Sulfonyl-2-Pyridone / Pfizer

A drug design initiated the replacement of the aryl ring of the Roche's phenyl acetamide series with N-linked heterocycles as 4-sufonyl-2-pyridone. The detailed SAR was disclosed in Table 1-3. In spite of acceptable in vitro metabolic stability of representative compounds, these compounds exhibited very high clearance, short half-lives, and poor BA in vivo. Careful examination elucidated 4-Sulfonyl-2-Pyridone substructure could be easily glutathione-conjugated even in the absence of any metabolic activation condition.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4W6Y343-1-3&_cdi=5221&_user=2645672&_o...

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tfujimoto
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MK-0457 (VX-680), the Potent Aurora Kinase Inhibitor / Vertex, Merck

MK-0457, the first-in-class potent aurora kinase inhibitor, was disclosed.

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4W6YJ6X-4-3&_cdi=5221&_user=2645672&_o...


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tfujimoto
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Orally Bioavailable Alkyl Amines Renin Inhibitors / Vitae

Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral adminstration of lead compound 21l, with MW of 508 and IC50 of 0.47 nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-4W741X3-4-1&_cdi=5221&_user=2645672&_o...

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tfujimoto
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Tetrasubstituted Imidazolines NPY Antagonists / Banyu

Drug design was focused on metabolically stable potent NPY5 R antagonists without hERG inhibition. It is interesting that methyl insertion of 5 position of imidazoline improved potency and reduced hERG inhibition. Reduced lipophilicity strategy also succeeded in reduction of hERG inhibition. In addition, it should be noted that an excellent correlation was observed between the log D values and CSF-to-brain ratios. It is an useful knowledge that this correlation is generally valid for a series of structurally close analogues that have similar pKa values, probably because basicity is an important parameter that significantly influences brain tissue binding.

http://pubs.acs.org/doi/pdf/10.1021/jm900110t

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