85102-92-7Relevant academic research and scientific papers
Preparation of a clinically investigated ras farnesyl transferase inhibitor
Maligres, Peter E.,Waters, Marjorie S.,Weissman, Steven A.,McWilliams, J. Christopher,Lewis, Stephanie,Cowen, Jennifer,Reamer, Robert A.,Volante,Reider, Paul J.,Askin, David
, p. 229 - 241 (2007/10/03)
The synthesis of ras farnesyl-protein transferase inhibitor 1 is described on a multi-kilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2 and a piperazinone 3 as viable precursors. The 1,5-disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5-disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prepare the arylpiperazinone fragment 3.
Synthesis and calcium antagonist activity of new 1,4-dihydropyridines containing nitrobenzylimidazolyl substituent in ginea-pig ileal smooth muscle
Zarghi,Derakhshandeh,Roshanzamir,Jorjani,Rastegar,Varmazyari,Shafiee
, p. 15 - 20 (2007/10/03)
New alkyl ester analogues of nifedipine, in which the ortho-nitrophenyl group of position 4 is replaced by 1-(4-nitrobenzyl)-5-imidazolyl or 2-methylthio-1-(4-nitrobenzyl)-5-imidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the electrically induced contraction of guinea-pig ileal longitudinal smooth muscle. Our results demonstrate that all compounds inhibited the contractile response of guinea-pig ileum to electrical stimulation and the IC50 value of the most potent compounds 6a and 6f were significantly lower than that of nifedipine. Therefore, they are more potent than nifedipine.
Process for making 1,5-disubstituted imidazoles
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, (2008/06/13)
The present invention is directed to a process for synthesizing 1,5-disubstituted imidazoles, which are useful in the preparation of farnesyl-protein transferase inhibitors.
The Discovery of Potent Nonpeptide Angiotensin II Receptor Antagonists: A New Class of Potent Antihypertensives
Duncia, John V.,Chiu, Andrew T.,Carini, David J.,Gregory, George B.,Johnson, Alexander L.,et al.
, p. 1312 - 1329 (2007/10/02)
A new class of potent antihypertensives has been discovered that exert their effect through blockade of the angiotensin II (AII) receptor.Most AII antagonists reported so far are peptide mimics of the endogenous vasoconstrictor octapeptide angiotensin II.The compounds of this paper are nonpeptides and therefore constitute a new class of potent AII receptor antagonists.Based on the overlap of a conformation of AII with literature lead 3, a hypothesis was developed suggesting the need for an additional acidic functionality to increase the lead's potency.The substitution of an additional carboxylic acid resulted in a 10-fold increase in binding affinity observed for diacid 4.The binding affinities for subsequent compounds were eventually increased 1000-fold over that of the literature leads through a systematic SAR study.Thus the AII receptor binding affinity 50 (μM)> of 15 μM for literature lead 1, for example, was increased to 0.018 and 0.012 μM for compounds 33 and 53.A structure-affinity relationship has been found requiring the presence of four key elements for good activity: (1) an additional phenyl ring at the N-benzyl para position of the benzylimidazole nucleus, (2) an acidic functionality at the ortho position of the terminal aromatic ring, (3) a lipophilic side chain at the imidazole 2-position of three to five carbon atoms in length, and (4) a group at the imidazole 5-position capable of hydrogen bonding.The synthesis as well as the pharmacological activity of the compounds in this new series of AII receptor antagonists are presented.
