65202-60-0Relevant academic research and scientific papers
Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099)
Basarab, Gregory S.,Hill, Pamela J.,Garner, C. Edwin,Hull, Ken,Green, Oluyinka,Sherer, Brian A.,Dangel, P. Brian,Manchester, John I.,Bist, Shanta,Hauck, Sheila,Zhou, Fei,Uria-Nickelsen, Maria,Illingworth, Ruth,Alm, Richard,Rooney, Mike,Eakin, Ann E.
, p. 6060 - 6082 (2014/08/18)
AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.
PYRROLE DERIVATIVES WITH ANTIBACTERIAL ACTIVITY
-
, (2008/06/13)
Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.
Heterocyclic compounds
-
, (2008/06/13)
The compound Ia STR1 has been shown to possess GABA-related activity. The invention relates to Ia and derivatives thereof, covered by the formula STR2 in which R" is hydrogen, acetyl or a group of the general formula STR3 in which R5 is C1-8 alkyl; phenyl; phenyl substituted in the 4-position with halogen, lower alkoxy, or lower alkyl; or phenylalkyl in which the phenyl group may be substituted in the 4-position with halogen, lower alkoxy, or lower alkyl; and salts thereof. Novel intermediates for preparing I are STR4 in which Alk is a lower alkyl group and Z is hydrogen or an amino-protecting group; STR5 wherein Z is hydrogen or an amino-protecting group, T is a group convertible, by hydrolysis, into an oxy group, and Q is a leaving group which, on reaction with hydroxylamine, forms a hydroxamic acid group; STR6 wherein Z and T are as defined above; STR7 wherein Z is as defined above, and W is hydrogen or a group removable to yield the free hydroxy group, with the proviso that at least one of Z and W is different from hydrogen.
