- Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability
-
We have identified GR138950, a potent antagonist of the angiotensin II receptor with high oral bioavailability, as our second drug candidate to GR117289. Using GR117289, a compound with moderate bioavailability (20%) in man as a lead, we pursued a strategy aimed at enhancing bioavailability. The strategy was based on SAR established around the diacid GR117289, and from this, it was proposed that a monoacid, in particular a trifluoromethanesulfonamide, should be better absorbed after oral administration and have enhanced oral bioavailability. This led to the identification of GR138950, a potent antihypertensive agent in the renal hypertensive rat, causing sustained falls in blood pressure after oral administration. Oral bioavailability of GR138950 in rats and dogs is high, confirming that GR138950 is well absorbed after oral administration. Moreover, the low plasma clearance and long plasma half-life suggest that this compound will be suitable for once a day administration. Furthermore, the preliminary data indicate that the high bioavailability of GR138950 seen in rats and dogs translates to man. These results demonstrate clearly that GR138950 has the potential to be a clinically effective antihypertensive agent. Further studies are in progress to evaluate GR138950 in the treatment of hypertension.
- Judd,Dowle,Middlemiss,Scopes,Ross,Jack,Pass,Tranquillini,Hobson,Panchal,Stuart,Paton,Hubbard,Hilditch,Drew,Robertson,Clark,Travers,Hunt,et al.
-
-
Read Online
- The development of a manufacturing route for the GPIIb/IIIa receptor antagonist SB-214857-A. Part 1: Synthesis of the key intermediate 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester, SB-235349
-
The development of an efficient manufacturing route to 2,3,4,5-tetrahydro-4-methyl-3-Oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester SB-235349, a key intermediate in the synthesis of lotrafiban is described. The synthesis starts with 2-nitrobenzyl alcohol which is mesylated, reacted with methylamine and then dimethylacetylene dicarboxylate followed by reduction of the nitro group. Treatment of the resultant aniline with acid gives an intermediate quinazoline which rearranges on treatment with base to give a 1,4-benzodiazapine. Reduction of the exocyclic double bond affords SB-235349. The process can be run without isolation of any of the intermediates and has been used to prepare several tons of SB-235349.
- Andrews, Ian P.,Atkins, Richard J.,Breen, Gary F.,Carey, John S.,Forth, Michael A.,Morgan, David O.,Shamji, Amin,Share, Andrew C.,Smith, Stephen A. C.,Walsgrove, Timothy C.,Wells, Andrew S.
-
-
Read Online
- Preparation method 1 - (2 -nitrobenzyl) pyrrole -2 - formaldehyde
-
The invention discloses a preparation method of 1 - (2 -nitrobenzyl) pyrrole -2 - formaldehyde, which comprises the following steps: S1. 1 Nitrobenzene-based methanol, triethylamine and dichloromethane are added to the reaction kettle 2 - stirred at - 5 °
- -
-
Paragraph 0040; 0098-0099; 0102-0103; 0106-0107
(2021/10/11)
-
- NOVEL SIRT 1 ACTIVATOR AND MEDICINAL USE THEREOF
-
The present invention relates to a SIRT 1 activator and medical use thereof and in the present invention, a novel SIRT 1 activator compound based on benzo[d]furan or a benzo[d]oxazole backbone, a crystalline form thereof, a hydrate thereof, or a salt thereof was prepared, and that the compound has obesity, insulin resistance and dyslipidemia improvement effect, fatty liver improvement effect, cell aging protection, oxidative stress protection and yeast life extension effect, collagen synthesis and wrinkle improvement effect, was confirmed. Therefore, the novel SIRT 1 activator compound having the above-mentioned effect is usefully used as a pharmaceutical composition for preventing or treating metabolic diseases including obesity, diabetes, dyslipidemia, etc., or liver diseases including alcoholic or non-alcoholic fatty liver, fatty hepatitis, etc., a cosmetic composition for preventing or improving wrinkles, a health food composition for improving cell aging or extending lifespan, and the like.
- -
-
Paragraph 0043; 0046
(2020/03/13)
-
- Structure-activity relationship of the cinnamamide family of antibiotic potentiators for methicillin-resistant: Staphylococcus aureus (MRSA)
-
Methicillin-resistant Staphylococcus aureus (MRSA) is a global public health threat. MRSA has evolved a complex set of biochemical processes that mobilize the organism for inducible resistance on challenge by β-lactam antibiotics. Interfering pharmacologi
- Speri, Enrico,Fishovitz, Jennifer,Mobashery, Shahriar
-
p. 2008 - 2016
(2019/01/04)
-
- Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry
-
The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC50 value of 0.089 ± 0.007 μM, which was two orders of magnitude lower than that of bestatin (IC50 = 9.4 ± 0.5 μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10 μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100 μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.
- Cao, Jiangying,Ma, Chunhua,Zang, Jie,Gao, Shuai,Gao, Qianwen,Kong, Xiujie,Yan, Yugang,Liang, Xuewu,Ding, Qin'ge,Zhao, Chunlong,Wang, Binghe,Xu, Wenfang,Zhang, Yingjie
-
p. 3145 - 3157
(2018/06/01)
-
- A new synthesis of the GPIIb/IIIa receptor antagonist SB-214857-A
-
A new synthesis of lotrafiban SB-214857-A is reported. The key steps are the preparation of racemic (4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-acetic acid methyl ester from 2-nitrobenzyl alcohol, a resolution using an immobilised li
- Andrews, Ian P,Atkins, Richard J,Badham, Neil F,Bellingham, Richard K,Breen, Gary F,Carey, John S,Etridge, Stephen K,Hayes, Jerome F,Hussain, Nigel,Morgan, David O,Share, Andrew C,Smith, Stephen A.C,Walsgrove, Timothy C,Wells, Andrew S
-
p. 4915 - 4917
(2007/10/03)
-