- COMPOUNDS AND METHODS FOR INHIBITION OF MULTIPLE MYELOMA
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Novel compounds (small molecules) that potently and selectively inhibit MMP-13 (i.e., MMP-13 inhibitors) are used for treatment of multiple myeloma. The MMP-13 inhibitors described herein are highly selective for MMP-13 and when administered to an individ
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Page/Page column 0033
(2020/03/23)
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- Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H 4 receptor antagonists
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This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.
- Savall, Brad M.,Chavez, Frank,Tays, Kevin,Dunford, Paul J.,Cowden, Jeffery M.,Hack, Michael D.,Wolin, Ronald L.,Thurmond, Robin L.,Edwards, James P.
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p. 2429 - 2439
(2014/04/17)
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- Direct synthesis of 5- and 6-substituted 2-aminopyrimidines as potential non-natural nucleobase analogues
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A series of 2-aminopyrimidine derivatives, substituted at 5- and 6-positions, were synthesized. The reaction was carried out in a single step by treatment of the corresponding β-ketoester or β-aldehydoester with guanidine hydrochloride in the presence of K2CO3, in a microwave-assisted method without the requirement of solvent. A unique 1:1 co-crystal structure was obtained which shows that a 6-phenyl-2- aminopyrimidinone forms a strong nucleobase-pair with cytosine, involving three hydrogen bonds. The base-pair was found to be as strong as that of natural guanine:cytosine (G:C), signifying the potential application of the synthesized derivatives. Additionally, we also report a second co-crystal involving 5-isopropyl-6-methyl-2-aminopyrimidinone and cytosine in a 1:1 ratio, which also shows strong base-pairing properties. the Partner Organisations 2014.
- Radhakrishnan,Sharma, Namita,Kundu, Lal Mohan
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p. 15087 - 15090
(2014/04/17)
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- Structure-activity relationship and in vitro and in vivo evaluation of the potent cytotoxic anti-microtubule agent N-(4-methoxyphenyl)-N,2,6-trimethyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-aminium chloride and its analogues as antitumor agents
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A series of 21 substituted cyclopenta[d]pyrimidines were synthesized as an extension of our discovery of the parent compound (±)-1·HCl as an anti-microtubule agent. The structure-activity relationship indicates that the N-methyl and a 4N-methoxy groups appear important for potent activity. In addition, the 6-substituent in the parent analogue is not necessary for activity. The most potent compound 30·HCl was a one to two digit nanomolar inhibitor of most tumor cell proliferations and was up to 7-fold more potent than the parent compound (±)-1·HCl. In addition, 30·HCl inhibited cancer cell proliferation regardless of Pgp or βIII-tubulin status, both of which are known to cause clinical resistance to several anti-tubulin agents. In vivo efficacy of 30·HCl was demonstrated against a triple negative breast cancer xenograft mouse model. Compound 30·HCl is water-soluble and easily synthesized and serves as a lead compound for further preclinical evaluation as an antitumor agent.
- Gangjee, Aleem,Zhao, Ying,Raghavan, Sudhir,Rohena, Cristina C.,Mooberry, Susan L.,Hamel, Ernest
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p. 6829 - 6844
(2013/10/01)
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