- Iridium-catalysed C-H borylation of β-aryl-aminopropionic acids
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Iridium-catalysed catalytic, regioselective C-H borylation of β-aryl-aminopropionic acid derivatives gives access to 3,5-functionalised protected β-aryl-aminopropionic acid boronates. The synthetic versatility of these new boronates is demonstrated through sequential one-pot functionalisation reactions to give diverse building blocks for medicinal chemistry. The C-H borylation is also effective for dipeptide substrates. We have exemplified this methodology in the synthesis of a pan αv integrin antagonist.
- MacDonald, Simon J. F.,Nortcliffe, Andrew,Robinson, Henry,Simelis, Klemensas,Stillibrand, Joe
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supporting information
p. 6696 - 6701
(2020/09/21)
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- Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents
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Antagonism of αvβ6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an αvβ3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved αvβ6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan αv antagonists having ca. 100 nM potency against αvβ3, αvβ5, αvβ6, and αvβ8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for αvβ3 and αvβ5.
- Adams, James,Anderson, Edward C.,Blackham, Emma E.,Chiu, Yin Wa Ryan,Clarke, Thomas,Eccles, Natasha,Gill, Luke A.,Haye, Joshua J.,Haywood, Harvey T.,Hoenig, Christian R.,Kausas, Marius,Le, Joelle,Russell, Hannah L.,Smedley, Christopher,Tipping, William J.,Tongue, Tom,Wood, Charlotte C.,Yeung, Jason,Rowedder, James E.,Fray, M. Jonathan,McInally, Thomas,Macdonald, Simon J. F.
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supporting information
p. 1207 - 1212
(2015/04/27)
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- Burkholderia cepacia lipase is an excellent enzyme for the enantioselective hydrolysis of β-heteroaryl-β-amino esters
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The enantioselective (E >200) lipase PS-catalysed hydrolysis of β-heteroaryl-β-amino esters is described. The reactions were performed with H2O (0.5 equiv) in either diisopropyl ether or tert-butyl methyl ether at 25 °C. The resulting β-heteroaryl-substituted β-amino acid enantiomers were formed in high enantiomeric excess (ee ≥ 97%) and in good yield (≥40%).
- Tasnadi, Gabor,Forro, Eniko,Fueloep, Ferenc
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experimental part
p. 1771 - 1777
(2009/12/28)
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- Competitive formation of β-amino acids, propenoic, and ylidenemalonic acids by the Rodionov reaction from malonic acid, aldehydes, and ammonium acetate in alcoholic medium
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The Rodionov reaction of 49 available aliphatic and aromatic aldehydes with malonic acid and ammonium acetate in alcoholic medium, resulting in formation of β-amino acids, propenoic, and ylidenemalonic acids, was studied. Certain regioselectivity regularities of the reaction were revealed. Among the variety of ketones studied, cyclohexanone is the only whose reaction yields a β-amino acid. Unusual dehydrofluorination of 6-chloro-2-fluorocinnamic acid under the Rodionov reaction was discovered. 2005 Pleiades Publishing, Inc.
- Lebedev,Lebedeva,Sheludyakov,Kovaleva,Ustinova,Kozhevnikov
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p. 1113 - 1124
(2007/10/03)
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- Structure-activity relationships of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists
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SAR studies of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists resulted in potent compounds. The best compound from the series had a binding affinity of 2 nM.
- Guo, Zhiqiang,Wu, Dongpei,Zhu, Yun-Fei,Tucci, Fabio C.,Regan, Collin F.,Rowbottom, Martin W.,Struthers, R. Scott,Xie, Qiu,Reijmers, Shelby,Sullivan, Susan K.,Sai, Yang,Chen, Chen
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p. 3685 - 3690
(2007/10/03)
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- Heterocyclic glycyl β-alanine derivatives
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The present invention relates to a class of compounds represented by the Formula I or a pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of treating conditions mediated by the αvβ3integrin.
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- 2-CYANOPYRROLES AND THEIR ANALOGUES AS DDP-IV INHIBITORS
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The present invention relates to therapeutically active and selective inhibitors of the enzyme DPP-IV having the formula I: (I) The invention furthermore relates to pharmaceutical compositions comprising the compounds and the use of such compounds for the manufacture of medicaments for treating diseases that are associated with proteins which are subject to inactivation by DPP-IV, such as type 2 diabetes and obesity.
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Page/Page column 32
(2010/02/08)
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- Process of preparing 3S-3-amino-3-aryl proprionic acid and derivatives thereof
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The present invention is directed to a process for preparing 3S-3-amino-3-aryl propionic acid and derivatives thereof.
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- META-GUANIDINE, UREA, THIOUREA OR AZACYCLIC AMINO BENZOIC ACID DERIVATIVES AS INTEGRIN ANTAGONISTS
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The present invention relates to a class of compounds represented by the Formula Ior a pharmaceutically acceptable salt thereof, whereinA ispharmaceutical compositions thereof and methods of using such compounds and compositions as alphavbeta3 antagonists.
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- An expedient method for resolution of 3-amino-3-(3′-pyridyl)propionic acid and related compounds
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Preparation of methyl (S)-3-amino-3-(3′-pyridyl)propionate dihydrochloride in high enantiomeric purity by selective crystallization of a diastereomeric salt of a carboxylic acid precursor (W-BOC-protected) with (1R,2S)-(-)-ephedrine is described. Further demonstration of the usefulness of this procedure to resolve other 3-amino-3-[(substituted)pyridyl]propionic acids is also described.
- Boesch, Heinz,Cesco-Cancian, Sergio,Hecker, Leonard R.,Hoekstra, William J.,Justus, Michael,Maryanoff, Cynthia A.,Scott, Lorraine,Shah, Rekha D.,Solms, Guenter,Sorgi, Kirk L.,Stefanick, Stephen M.,Thurnheer, Urs,Villani Jr., Frank J.,Walker, Donald G.
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- Potent, orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure-activity studies leading to the discovery of RWJ-53308
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Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-activity surrounding the prototype fibrinogen receptor antagonist RWJ-50042 (racemate of 1), which was derived from a unique approach involving the γ-chain of fibrinogen (Hoekstra et al. J. Med. Chem. 1995, 38, 1582). Our analogue studies culminated in the discovery of RWJ-53308 (2), a potent, orally active GPIIb/IIIa antagonist. To progress from RWJ-50042 to a suitable candidate for clinical development, we conducted a series of optimization cycles that employed solid-phase parallel synthesis for the rapid, efficient preparation of nearly 250 analogues, which were assayed for fibrinogen receptor affinity and inhibition of platelet aggregation induced by four different activators. This strategy produced several promising analogues for advanced study, including 3-(3,4- methylenedioxybenzene)-β-amino acid analogue 3 (significant improved in vivo potency) and 3-(3-pyridyl)-β-amino acid 2 (significantly improved potency, oral absorption, and duration of action). In dogs, 2 displayed significant ex vivo antiplatelet activity on oral administration at 1.0 mg/kg, 16% systemic oral bioavailability, minimal metabolic transformation, and an excellent safety profile. Additionally, 2 was found to be efficacious in three in vivo thrombosis models: canine arteriovenous (AV) shunt (0.01-0.1 mg/kg, iv), guinea pig photoactivation-induced injury (0.3-3 mg/kg, iv), and guinea pig ferric chloride-induced injury (0.3-1 mg/kg, iv). On the basis of its noteworthy preclinical data, RWJ-53308 (2) was selected for clinical evaluation.
- Hoekstra, William J.,Maryanoff, Bruce E.,Damiano, Bruce P.,Andrade-Gordon, Patricia,Cohen, Judith H.,Costanzo, Michael J.,Haertlein, Barbara J.,Hecker, Leonard R.,Hulshizer, Becky L.,Kauffman, Jack A.,Keane, Patricia,McComsey, David F.,Mitchell, John A.,Scott, Lorraine,Shah, Rekha D.,Yabut, Stephen C.
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p. 5254 - 5265
(2007/10/03)
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- Platelet aggregation inhibitors
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This invention herein relates to compounds having the following formula STR1 or a pharmaceutically acceptable salt thereof which are useful in the inhibition of platelet aggregation, to pharmaceutical compositions containing the compound and to a method o
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- Guanidinoalkyl glycine β-amino acids useful for inhibiting tumor metastasis
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This invention herein relates to a method of treating a condition mediated by inhibition of αv β3 integrins and a method of inhibiting tumor metastasis by administering a therapeutically effective amount of a compound having the foll
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- Guanidinoalkyl glycine β-amino acids useful for inhibiting bone loss
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This invention herein relates to a method of inhibiting bone resorption by administering a therapeutically effective amount of a compound having the following formula STR1 or a pharmaceutically acceptable salt thereof.
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