170170-13-5Relevant articles and documents
Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents
Shah, Khushbu,Lin, Xin,Queener, Sherry F.,Cody, Vivian,Pace, Jim,Gangjee, Aleem
, p. 2640 - 2650 (2018)
To combine the potency of trimetrexate (TMQ) or piritrexim (PTX) with the species selectivity of trimethoprim (TMP), target based design was carried out with the X-ray crystal structure of human dihydrofolate reductase (hDHFR) and the homology model of Pneumocystis jirovecii DHFR (pjDHFR). Using variation of amino acids such as Met33/Phe31 (in pjDHFR/hDHFR) that affect the binding of inhibitors due to their distinct positive or negative steric effect at the active binding site of the inhibitor, we designed a series of substituted-pyrrolo[2,3-d]pyrimidines. The best analogs displayed better potency (IC50) than PTX and high selectivity for pjDHFR versus hDHFR, with 4 exhibiting a selectivity for pjDHFR of 24-fold.
PYRIMIDINE COMPOUNDS AND PYRIMIDO INDOLE COMPOUNDS AND METHODS OF USE
-
Page/Page column 44, (2016/03/19)
The present invention discloses substituted pyrimidine and pyrimido indole compounds and optionally pharmaceutically acceptable salts, hydrates or solvates thereof. A method of treating a patient having cancer or a disease comprising administering to a patient an effective amount of the compound or pharmaceutically acceptable salt, hydrate, or solvate thereof.
CoMFA analysis of tgDHFR and rlDHFR based on antifolates with 6-5 fused ring system using the all-orientation search (AOS) routine and a modified cross-validated r2-guided region selection (q2-GRS) routine and its initial application
Gangjee, Aleem,Lin, Xin,Biondo, Lisa R.,Queener, Sherry F.
scheme or table, p. 1684 - 1701 (2010/04/29)
We report the development of CoMFA analysis models that correlate the 3D chemical structures of 80 compounds with 6-5 fused ring system synthesized in our laboratory and their inhibitory potencies against tgDHFR and rlDHFR. In addition to conventional CoMFA analysis, we used two routines available in the literature aimed at the optimization of CoMFA: all-orientation search (AOS) and cross-validated r2-guided region selection (q2-GRS) to further optimize the models. During this process, we identified a problem associated with q2-GRS routine and modified using two strategies. Thus, for the inhibitory activity against each enzyme (tgDHFR and rlDHFR), five CoMFA models were developed using the conventional CoMFA, AOS optimized CoMFA, the original q2-GRS optimized CoMFA and the modified q2-GRS optimized CoMFA using the first and the second strategy. In this study, we demonstrate that the modified q2-GRS routines are superior to the original routine. On the basis of the steric contour maps of the models, we designed four new compounds in the 2,4-diamino-5-methyl-6-phenylsulfanyl-substituted pyrrolo[2,3-d]pyrimidine series. As predicted, the new compounds were potent and selective inhibitors of tgDHFR. One of them, 2,4-diamino-5-methyl-6-(2′,6′-dimethylphenylthio)pyrrolo[2,3-d]pyrimidine, is the first 6-5 fused ring system compound with nanomolar tgDHFR inhibitory activity. The HCl salt of this compound was also prepared to increase solubility. Both forms of the drug were tested in vivo in a Toxoplasma gondii infection mouse model. The results indicate that both forms were active with the HCl salt significantly more potent than the free base.
Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3 H -quinazolin-6-yl)methylprop-2- ynylamino]- N -(3-pyridylmethyl)benzamide (CB-30865) as potent inhibitors of nicotinamide phosphoribosyltransferase (Nampt)
Lockman, Jeffrey W.,Murphy, Brett R.,Zigar, Daniel F.,Judd, Weston R.,Slattum, Paul M.,Gao, Zhong-Hua,Ostanin, Kirill,Green, Jeremy,McKinnon, Rena,Terry-Lorenzo, Ryan T.,Fleischer, Tracey C.,Boniface, J. Jay,Shenderovich, Mark,Willardsen, J. Adam
experimental part, p. 8734 - 8746 (2011/02/23)
We have shown previously that the target of the potent cytotoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino] -N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridylmethylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C2 of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.
A one-step ring transformation/ring annulation approach to pyrrolo[2,3-d]pyrimidines. A new synthesis of the potent DHFR inhibitor TNP-351
Taylor,Patel,Jun
, p. 6684 - 6687 (2007/10/03)
Condensation of amidines with 2-amino-3-cyanofurans gives 2-substituted-4-aminopyrrolo[2,3-d]pyrimidines by a ring-opening, ring-recyclization sequence of reactions through which the starting furan 2-amino nitrogen becomes the pyrrole nitrogen of the final product and one of the amidine nitrogens becomes N-1 of the fused pyrimidine ring. 2,4-Diamino-5-[2-(4-carbethoxyphenyl)ethyl]pyrrolo[2,3-d]pyrimidine, a key intermediate in the synthesis of the DHFR inhibitor TNP-351, has been prepared in one step by reaction of ethyl 4-[2-(2-amino-3-cyanofuran-4-yl)ethyl]benzoate with guanidine.
