136159-62-1Relevant articles and documents
Design, Synthesis, and Pharmacokinetic Evaluation of Phosphate and Amino Acid Ester Prodrugs for Improving the Oral Bioavailability of the HIV-1 Protease Inhibitor Atazanavir
Subbaiah, Murugaiah A.M.,Mandlekar, Sandhya,Desikan, Sridhar,Ramar, Thangeswaran,Subramani, Lakshumanan,Annadurai, Mathiazhagan,Desai, Salil D.,Sinha, Sarmistha,Jenkins, Susan M.,Krystal, Mark R.,Subramanian, Murali,Sridhar, Srikanth,Padmanabhan, Shweta,Bhutani, Priyadeep,Arla, Rambabu,Singh, Shashyendra,Sinha, Jaydeep,Thakur, Megha,Kadow, John F.,Meanwell, Nicholas A.
supporting information, p. 3553 - 3574 (2019/04/17)
Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. Val amino acid and Val-Val dipeptides imparted low plasma exposure of the parent, although the exposure of the prodrugs was high, reflecting good absorption. Screening of additional amino acids resulted in the identification of an l-Phe ester that offered an improved exposure of 1 and reduced levels of the circulating prodrug. Further molecular editing focusing on the linker design culminated in the discovery of the self-immolative l-Phe-Sar dipeptide derivative 74 that gave four-fold improved AUC and eight-fold higher Ctrough values of 1 compared with oral administration of the drug itself, demonstrating a successful prodrug approach to the oral delivery of 1.
Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using N-Boc-N-Bn-Protected α-Amino Aldehydes
Haghshenas, Pouyan,Quail, J. Wilson,Gravel, Michel
, p. 12075 - 12083 (2016/12/23)
The effectiveness of utilizing N-Bn-N-Boc-α-amino aldehydes in cross-benzoin reactions with heteroaromatic aldehydes is demonstrated. The reaction is both chemoselective and syn-selective, making it complementary to the anti-selective cross-benzoin reaction of NHBoc-α-amino aldehydes. Good diastereoselectivity is obtained for a variety of amino aldehydes, including nonhindered ones. A Felkin-Anh model can be used to rationalize the observed diastereoselectivity.
Base-promoted c→n acyl rearrangement: An unconventional approach to α-amino acid derivatives
Ugarriza, Iratxe,Uria, Uxue,Carrillo, Luisa,Vicario, Jose L.,Reyes, Efraim
, p. 11650 - 11654 (2014/10/15)
We have discovered that N-alkyl aminomalonates undergo a fast and selective intramolecular C→N acyl rearrangement reaction in the presence of a strong base, leading to N-protected glycinates in excellent yield. Moreover, the fact that the reaction proceeds through a nucleophilic enolate intermediate has been used for implementing a tandem rearrangement/alkylation sequence that has been applied to the preparation of synthetically relevant nonproteinogenic tertiary and quaternary N-alkyl α-amino acids in a very simple and reliable way.
