Elfatih Elzein | Gilead - Academia.edu (original) (raw)
Papers by Elfatih Elzein
The present disclosure provides a process for the preparation of 2-adenosine N-pyrazole compounds... more The present disclosure provides a process for the preparation of 2-adenosine N-pyrazole compounds exemplified by the structure shown below that are potent and selective agonists for A.sub.2A adenosine receptor, compositions comprising these compounds, and methods for using these compounds to stimulate mammalian coronary vasodilation for imaging the heart
Current Pharmaceutical Design, 1996, 2, 263-280 263 Classical and Nonclassical Antifolates as Pot... more Current Pharmaceutical Design, 1996, 2, 263-280 263 Classical and Nonclassical Antifolates as Potential Antitumor, Antipneumocystis and Antitoxoplasma Agents Aleem Gangjee*, Elfatih Elzein, Mohit Kothare and Anil Vasudevan Division of Medicinal Chemistry, Graduate ...
Handbook of Experimental Pharmacology, 2009
Intense efforts of many pharmaceutical companies and academicians in the A(1) adenosine receptor ... more Intense efforts of many pharmaceutical companies and academicians in the A(1) adenosine receptor (AR) field have led to the discovery of clinical candidates that are antagonists, agonists, and allosteric enhancers. The A(1)AR antagonists currently in clinical development are KW3902, BG9928, and SLV320. All three have high affinity for the human (h) A(1)AR subtype (hA(1) K (i) < 10 nM), > 200-fold selectivity over the hA(2A) subtype, and demonstrate renal protective effects in multiple animal models of disease and pharmacologic effects in human subjects. In the A(1)AR agonist area, clinical candidates have been discovered for the following conditions: atrial arrhythmias (tecadenoson, selodenoson and PJ-875); Type II diabetes and insulin sensitizing agents (GR79236, ARA, RPR-749, and CVT-3619); and angina (BAY 68-4986). The challenges associated with the development of any A(1)AR agonist are to obtain tissue-specific effects but avoid off-target tissue side effects and A(1)AR desensitization leading to tachyphylaxis. For the IV antiarrhythmic agents that act as ventricular rate control agents, a selective response can be accomplished by careful IV dosing paradigms. The treatment of type II diabetes using A(1)AR agonists in the clinic has met with limited success due to cardiovascular side effects and a well-defined desensitization of full agonists in human trials (GR79236, ARA, and RPR 749). However, new partial A(1)AR agonists are in development, including CVT-3619 hA(1) AR K(i) = 55nM, hA(2A:hA2B:hA(3))1,000:20, CV Therapeutics), which have the potential to provide enhanced insulin sensitivity without cardiovascular side effects and tachyphylaxis. The nonnucleosidic A(1)AR agonist BAY 68-4986 (capadenoson) represents a novel approach to angina wherein both animal studies and early human studies are promising. T-62 is an A(1)AR allosteric enhancer that is currently being evaluated in clinical trials as a potential treatment for neuropathic pain. The challenges associated with developing A(1)AR antagonists, agonists, or allosteric enhancers for therapeutic intervention are now well defined in humans. Significant progress has been made in identifying A(1)AR antagonists for the treatment of edema associated with congestive heart failure (CHF), A(1)AR agonists for the treatment of atrial arrhythmias, type II diabetes and angina, and A(1)AR allosteric enhancers for the treatment of neuropathic pain.
Journal of Medicinal Chemistry, 2006
Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is beli... more Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A(2B) adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A(2B) AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A(2B) AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (K(i) = 9 nM) for the A(2B) AdoR, but it is only 2-fold selective versus the A(1) AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A(2B) AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF(3) at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A(2B) AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A(2B) AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A(2B) AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A(2B) AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (K(i) = 1 nM) A(2B) AdoR antagonist with high selectivity (990-, 690-, and 1,000-) for the human A(1), A(2A,) and A(3) AdoRs.
Journal of Medicinal Chemistry, 2008
Recently, we have reported a series of new 1,3-symmetrically (R 1 = R 3) substituted xanthines ( ... more Recently, we have reported a series of new 1,3-symmetrically (R 1 = R 3) substituted xanthines ( 3 and 4) which have high affinity and selectivity for the human adenosine A 2B receptors (hA(2B)-AdoR). Unfortunately, this class of compounds had poor pharmacokinetic properties. This prompted us to investigate the effect of differential alkyl substitution at the N-1 and N-3 positions ( N 1-R not equal to N 3-R) on A(2B)-AdoR affinity and selectivity; we had the dual objectives of enhancing affinity and selectivity for the A(2B)-AdoR, as well as improving oral bioavailability. This effort has led to the discovery of compound 62, that displayed high affinity and selectivity for the hA(2B)-AdoR (K(i) = 22 nM). In addition, compound 62 showed high functional potency in inhibiting the accumulation of cyclic adenosine monophosphate induced by 5'- N-ethylcarboxamidoadenosine in HEK-A(2B)-AdoR and NIH3T3 cells with K(B) values of 6 and 2 nM, respectively. In a single ascending-dose phase I clinical study, compound 62 had no serious adverse events and was well tolerated.
Journal of Medicinal Chemistry, 2004
We describe the synthesis of new high affinity and selective A(3)-adenosine receptor (A(3)-AdoR) ... more We describe the synthesis of new high affinity and selective A(3)-adenosine receptor (A(3)-AdoR) agonists. Introduction of a methyl group at the N(6)-position of the A(2A)-AdoR selective 2-pyrazolyl-adenosine analogues (Figure 2) brought about a substantial increase in the A(3)-AdoR binding affinity and selectivity. While the N(6)-desmethyl analogues 3a and 4 were inactive at the A(3)-AdoR (K(i) > 10 microM), the corresponding N(6)-methyl analogues 5 and 22 showed good binding affinity at the A(3)-AdoR (K(i) = 73 and 97 nM, respectively). Replacement of the carboxamide group in 5 with different heteroaryl groups resulted in analogues with high affinities and selectivity for the A(3)-AdoR. (2R,3S,4R)-tetrahydro-2-(hydroxymethyl)-5-(6-(methylamino)-2-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)-9H-purin-9-yl)furan-3,4-diol (15, K(i) = 2 nM) displayed high selectivity for the A(3)-AdoR versus A(1)- and A(2A)-AdoRs (selectivity ratios of 1900 and >2000, respectively).
Journal of Medicinal Chemistry, 2001
Classical and nonclassical isosteric C8-N9 bridged analogues of the multitargeted antifolate LY23... more Classical and nonclassical isosteric C8-N9 bridged analogues of the multitargeted antifolate LY231514 were synthesized as inhibitors of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and as antitumor and antiopportunistic infection agents. The syntheses of the analogues were accomplished by reductive amination of the appropriate anilines with 2-amino-4-oxo-5-cyanopyrrolo[2,3-d]pyrimidine (28) followed by saponification of the ethyl esters, for the classical analogue 6. The N9-methyl analogues were obtained from the N9-H precursors by reductive methylation. In general, the nonclassical compounds 7-17 were similar in potency to TMP against Toxoplasma gondii DHFR, with selectivity ratios greater than 38 and 21 for 11 and 16, respectively. These compounds were poor inhibitors of Pneumocystis carinii DHFR and rat liver DHFR. The nonclassical analogues were also inactive against TS. The classical analogue 6 was a marginal inhibitor of isolated human TS (IC50 = 46 microM) and of human DHFR (IC50 = 10 microM), however, it was a potent inhibitor of the growth of two human head and neck squamous cell carcinoma cell lines and of CCRF-CEM human lymphoblastic leukemia cells in culture and was similar to LY231514 against ZR-75-1 human breast carcinoma cell line. Evaluation of 6 against MTX-resistant sublines indicated that DHFR is not the major target of 6. Metabolite protection studies of the growth inhibitory activity of 6 suggest that TS is a major target of this drug and that polyglutamyl forms of 6 may serve as the intracellular TS inhibitors. These studies also suggest that 6 has a site of action in addition to sites in the folate pathway.
Expert Opinion on Investigational Drugs, 2008
The challenges in developing any A(1) adenosine receptor (A(1)-AdoR) agonist involve having the d... more The challenges in developing any A(1) adenosine receptor (A(1)-AdoR) agonist involve having the desired effect on target tissue while avoiding side effects due to activation of A(1)-AdoR on other tissues. A(1)-AdoR de-sensitization leading to tachyphylaxis is also another challenge. The major goal of this review is twofold: to highlight the structure affinity relationships (SAR) of A(1)-AdoR agonists, starting with initial lead compounds that were the genesis for second-generation compounds with high selectivity, affinity, and partial agonism; and to give an overview of the A(1)-AdoR agonists under development for various indications. Intense efforts by many pharmaceutical companies and academicians in the A(1)-AdoR agonist field have led to the discovery of clinical candidates for the following conditions: atrial arrhythmias - Tecadenoson, Selodenoson and PJ-875; type 2 diabetes (T2D) and insulin-sensitizing agents - GR79236, ARA, and CVT-3619; pain management - SDZ WAG 994, GW493838; and angina - BAY-68-4986. For the i.v. antiarrhythmic agents that act as ventricular rate control agents, a selective response can be accomplished by careful dosing paradigms. The treatment of T2D using A(1)-AdoR agonists has been met by limited success due to cardiovascular side effects and well-defined desensitization of full agonists in both animal models and human trials (GR79236 and ARA). However, new partial A(1)-AdoR agonists are in development, including CVT-3619 (hA(1)-AdoR K(i) = 55 nm, selectivity A(2A) > 200; A(2B) > 1000; A(3) > 20, CV Therapeutics), that have the potential to provide enhanced insulin sensitivity without cardiovascular side effects or tachyphylaxis. The A(1)-AdoR agonists GW493838 and GR792363 are under evaluation for pain management. The non-nucleosidic A(1)-AdoR agonist, BAY-68-4986 (Capadenoson), represents a unique approach to angina wherein both animal studies and early human studies are promising. The challenges associated with developing an A(1)-AdoR agonist for therapeutic intervention are now well defined in humans. Significant progress has been made in identifying agents for the treatment of atrial arrhythmias, T2D, and angina.
Bioorganic & Medicinal Chemistry Letters, 2008
A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for the... more A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for their affinity for the adenosine receptors (AdoRs). We have discovered two compounds 18 (CVT-7124) and 28 (CVT-6694) that display good affinity for the A 2B AdoR (K i = 6 nM and 7 nM, respectively) and greater selectivity for the human A 1 , A 2A , and A 3 AdoRs (>1000-, >830-, and >1500-fold; >850-, >700-, and >1280-fold, respectively). CVT-6694 has been shown to block the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells (BSMC), a process believed to be promoted by activation of A 2B AdoR.
Bioorganic & Medicinal Chemistry Letters, 2002
Nucleic acids U 0700 Structure-Affinity Relationships of the Affinity of 2-Pyrazolyl Adenosine An... more Nucleic acids U 0700 Structure-Affinity Relationships of the Affinity of 2-Pyrazolyl Adenosine Analogues for the Adenosine A 2A Receptor. -Compounds such as (I) are prepared based on a modelling study. The structure-activity relationships are discussed. -(PALLE*, V. P.; ELZEIN*, E. O.; GOTHE, S. A.; LI, Z.; GAO, Z.; MEYER, S.; BLACKBURN, B.; ZABLOCKI, J. A.; Bioorg. Med. Chem. Lett. 12 (2002) 20,
Bioorganic & Medicinal Chemistry Letters, 2004
Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an e... more Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an estimated 2.3 million cases in the US (2001). A(1) adenosine receptor agonists can slow the electrical impulse propagation through the atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce ventricular rate. Compounds that are full agonists of the A(1) adenosine receptor can cause high grade AV block. Therefore, it is envisioned that a compound that is a partial agonist of the A(1) adenosine receptor could avoid this deleterious effect. 5(') Phenyl sulfides (e.g., 17, EC(50)=1.26 microM) and phenyl ethers (e.g., 28, EC(50)=0.2 microM) are partial agonists with respect to their AV nodal effects in guinea pig isolated hearts. Additional affinity, GTPgammaS binding data suggesting partial activity of the A(1) adenosine receptor, and PK results for 5(') modified adenosine derivatives are shown.
Bioorganic & Medicinal Chemistry Letters, 2004
New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles ... more New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles in the ÔWestern Por-tionÕ of the molecule. SAR studies led to the discovery of CVT-4325 (shown), a potent FOXi (IC 50 = 380 nM rat mitochondria) with favorable PK properties (F = 93%, t 1/2 = 13.6 h, dog).
Bioorganic & Medicinal Chemistry Letters, 2007
A series of new selective, high affinity A(1)-AdoR agonists is reported. Compound 23 that incorpo... more A series of new selective, high affinity A(1)-AdoR agonists is reported. Compound 23 that incorporated a carboxylic acid functionality in the 4-position of the pyrazole ring displayed K(iL) value of 1 nM for the A(1)-AdoR and >5000-fold selectivity over the A(3) and A(2A)-AdoRs. In addition, compound 19 that incorporated a carboxamide functionality in the 4-position of the pyrazole ring displayed subnanomolar affinity for the A(1)-AdoR (K(iL)=0.6 nM) and >600-fold selectivity over the A(3) and A(2A)-AdoRs.
Bioorganic & Medicinal Chemistry Letters, 2004
Bioorganic & Medicinal Chemistry Letters, 2006
A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A 2B ... more A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A 2B -AdoR antagonists have been synthesized and evaluated for their binding affinities for the A 2B , A 1 , A 2A , and A 3 -AdoRs. 8-(1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (K i = 1 nM) and selectivity for the A 2B -AdoR versus A 1 , A 2A , and A 3 -AdoRs (A 1 /A 2B , A 2A /A 2B , and A 3 /A 2B selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.
Nucleosides, Nucleotides and Nucleic Acids, 2001
Compound 20 (CVT-3146--a 2-[(N-1-(4-N-methylcarboxamidopyrazolyl)] adenosine derivative) and comp... more Compound 20 (CVT-3146--a 2-[(N-1-(4-N-methylcarboxamidopyrazolyl)] adenosine derivative) and compound 31 (CVT-3033--a 2-[(4-(1-N-pentylpyrazolyl)] adenosine derivative), were found to be short acting functionally selective coronary vasodilators (CV t0.5 = 5.2 +/- 0.2 and 3.4 +/- 0.5 min, respectively--rat isolated heart 50% reversal time) with good potency (EC50S = 6.4 +/- 1.2 nM and 67.9 +/- 16.7 nM, respectively), but they possess low affinity for the ADO A2A receptor (Ki = 1122 +/- 323 nM and 2138 +/- 952 nM, respectively; pig striatum).
The present disclosure provides a process for the preparation of 2-adenosine N-pyrazole compounds... more The present disclosure provides a process for the preparation of 2-adenosine N-pyrazole compounds exemplified by the structure shown below that are potent and selective agonists for A.sub.2A adenosine receptor, compositions comprising these compounds, and methods for using these compounds to stimulate mammalian coronary vasodilation for imaging the heart
Current Pharmaceutical Design, 1996, 2, 263-280 263 Classical and Nonclassical Antifolates as Pot... more Current Pharmaceutical Design, 1996, 2, 263-280 263 Classical and Nonclassical Antifolates as Potential Antitumor, Antipneumocystis and Antitoxoplasma Agents Aleem Gangjee*, Elfatih Elzein, Mohit Kothare and Anil Vasudevan Division of Medicinal Chemistry, Graduate ...
Handbook of Experimental Pharmacology, 2009
Intense efforts of many pharmaceutical companies and academicians in the A(1) adenosine receptor ... more Intense efforts of many pharmaceutical companies and academicians in the A(1) adenosine receptor (AR) field have led to the discovery of clinical candidates that are antagonists, agonists, and allosteric enhancers. The A(1)AR antagonists currently in clinical development are KW3902, BG9928, and SLV320. All three have high affinity for the human (h) A(1)AR subtype (hA(1) K (i) < 10 nM), > 200-fold selectivity over the hA(2A) subtype, and demonstrate renal protective effects in multiple animal models of disease and pharmacologic effects in human subjects. In the A(1)AR agonist area, clinical candidates have been discovered for the following conditions: atrial arrhythmias (tecadenoson, selodenoson and PJ-875); Type II diabetes and insulin sensitizing agents (GR79236, ARA, RPR-749, and CVT-3619); and angina (BAY 68-4986). The challenges associated with the development of any A(1)AR agonist are to obtain tissue-specific effects but avoid off-target tissue side effects and A(1)AR desensitization leading to tachyphylaxis. For the IV antiarrhythmic agents that act as ventricular rate control agents, a selective response can be accomplished by careful IV dosing paradigms. The treatment of type II diabetes using A(1)AR agonists in the clinic has met with limited success due to cardiovascular side effects and a well-defined desensitization of full agonists in human trials (GR79236, ARA, and RPR 749). However, new partial A(1)AR agonists are in development, including CVT-3619 hA(1) AR K(i) = 55nM, hA(2A:hA2B:hA(3))1,000:20, CV Therapeutics), which have the potential to provide enhanced insulin sensitivity without cardiovascular side effects and tachyphylaxis. The nonnucleosidic A(1)AR agonist BAY 68-4986 (capadenoson) represents a novel approach to angina wherein both animal studies and early human studies are promising. T-62 is an A(1)AR allosteric enhancer that is currently being evaluated in clinical trials as a potential treatment for neuropathic pain. The challenges associated with developing A(1)AR antagonists, agonists, or allosteric enhancers for therapeutic intervention are now well defined in humans. Significant progress has been made in identifying A(1)AR antagonists for the treatment of edema associated with congestive heart failure (CHF), A(1)AR agonists for the treatment of atrial arrhythmias, type II diabetes and angina, and A(1)AR allosteric enhancers for the treatment of neuropathic pain.
Journal of Medicinal Chemistry, 2006
Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is beli... more Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A(2B) adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A(2B) AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A(2B) AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (K(i) = 9 nM) for the A(2B) AdoR, but it is only 2-fold selective versus the A(1) AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A(2B) AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF(3) at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A(2B) AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A(2B) AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A(2B) AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A(2B) AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (K(i) = 1 nM) A(2B) AdoR antagonist with high selectivity (990-, 690-, and 1,000-) for the human A(1), A(2A,) and A(3) AdoRs.
Journal of Medicinal Chemistry, 2008
Recently, we have reported a series of new 1,3-symmetrically (R 1 = R 3) substituted xanthines ( ... more Recently, we have reported a series of new 1,3-symmetrically (R 1 = R 3) substituted xanthines ( 3 and 4) which have high affinity and selectivity for the human adenosine A 2B receptors (hA(2B)-AdoR). Unfortunately, this class of compounds had poor pharmacokinetic properties. This prompted us to investigate the effect of differential alkyl substitution at the N-1 and N-3 positions ( N 1-R not equal to N 3-R) on A(2B)-AdoR affinity and selectivity; we had the dual objectives of enhancing affinity and selectivity for the A(2B)-AdoR, as well as improving oral bioavailability. This effort has led to the discovery of compound 62, that displayed high affinity and selectivity for the hA(2B)-AdoR (K(i) = 22 nM). In addition, compound 62 showed high functional potency in inhibiting the accumulation of cyclic adenosine monophosphate induced by 5'- N-ethylcarboxamidoadenosine in HEK-A(2B)-AdoR and NIH3T3 cells with K(B) values of 6 and 2 nM, respectively. In a single ascending-dose phase I clinical study, compound 62 had no serious adverse events and was well tolerated.
Journal of Medicinal Chemistry, 2004
We describe the synthesis of new high affinity and selective A(3)-adenosine receptor (A(3)-AdoR) ... more We describe the synthesis of new high affinity and selective A(3)-adenosine receptor (A(3)-AdoR) agonists. Introduction of a methyl group at the N(6)-position of the A(2A)-AdoR selective 2-pyrazolyl-adenosine analogues (Figure 2) brought about a substantial increase in the A(3)-AdoR binding affinity and selectivity. While the N(6)-desmethyl analogues 3a and 4 were inactive at the A(3)-AdoR (K(i) > 10 microM), the corresponding N(6)-methyl analogues 5 and 22 showed good binding affinity at the A(3)-AdoR (K(i) = 73 and 97 nM, respectively). Replacement of the carboxamide group in 5 with different heteroaryl groups resulted in analogues with high affinities and selectivity for the A(3)-AdoR. (2R,3S,4R)-tetrahydro-2-(hydroxymethyl)-5-(6-(methylamino)-2-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)-9H-purin-9-yl)furan-3,4-diol (15, K(i) = 2 nM) displayed high selectivity for the A(3)-AdoR versus A(1)- and A(2A)-AdoRs (selectivity ratios of 1900 and >2000, respectively).
Journal of Medicinal Chemistry, 2001
Classical and nonclassical isosteric C8-N9 bridged analogues of the multitargeted antifolate LY23... more Classical and nonclassical isosteric C8-N9 bridged analogues of the multitargeted antifolate LY231514 were synthesized as inhibitors of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and as antitumor and antiopportunistic infection agents. The syntheses of the analogues were accomplished by reductive amination of the appropriate anilines with 2-amino-4-oxo-5-cyanopyrrolo[2,3-d]pyrimidine (28) followed by saponification of the ethyl esters, for the classical analogue 6. The N9-methyl analogues were obtained from the N9-H precursors by reductive methylation. In general, the nonclassical compounds 7-17 were similar in potency to TMP against Toxoplasma gondii DHFR, with selectivity ratios greater than 38 and 21 for 11 and 16, respectively. These compounds were poor inhibitors of Pneumocystis carinii DHFR and rat liver DHFR. The nonclassical analogues were also inactive against TS. The classical analogue 6 was a marginal inhibitor of isolated human TS (IC50 = 46 microM) and of human DHFR (IC50 = 10 microM), however, it was a potent inhibitor of the growth of two human head and neck squamous cell carcinoma cell lines and of CCRF-CEM human lymphoblastic leukemia cells in culture and was similar to LY231514 against ZR-75-1 human breast carcinoma cell line. Evaluation of 6 against MTX-resistant sublines indicated that DHFR is not the major target of 6. Metabolite protection studies of the growth inhibitory activity of 6 suggest that TS is a major target of this drug and that polyglutamyl forms of 6 may serve as the intracellular TS inhibitors. These studies also suggest that 6 has a site of action in addition to sites in the folate pathway.
Expert Opinion on Investigational Drugs, 2008
The challenges in developing any A(1) adenosine receptor (A(1)-AdoR) agonist involve having the d... more The challenges in developing any A(1) adenosine receptor (A(1)-AdoR) agonist involve having the desired effect on target tissue while avoiding side effects due to activation of A(1)-AdoR on other tissues. A(1)-AdoR de-sensitization leading to tachyphylaxis is also another challenge. The major goal of this review is twofold: to highlight the structure affinity relationships (SAR) of A(1)-AdoR agonists, starting with initial lead compounds that were the genesis for second-generation compounds with high selectivity, affinity, and partial agonism; and to give an overview of the A(1)-AdoR agonists under development for various indications. Intense efforts by many pharmaceutical companies and academicians in the A(1)-AdoR agonist field have led to the discovery of clinical candidates for the following conditions: atrial arrhythmias - Tecadenoson, Selodenoson and PJ-875; type 2 diabetes (T2D) and insulin-sensitizing agents - GR79236, ARA, and CVT-3619; pain management - SDZ WAG 994, GW493838; and angina - BAY-68-4986. For the i.v. antiarrhythmic agents that act as ventricular rate control agents, a selective response can be accomplished by careful dosing paradigms. The treatment of T2D using A(1)-AdoR agonists has been met by limited success due to cardiovascular side effects and well-defined desensitization of full agonists in both animal models and human trials (GR79236 and ARA). However, new partial A(1)-AdoR agonists are in development, including CVT-3619 (hA(1)-AdoR K(i) = 55 nm, selectivity A(2A) > 200; A(2B) > 1000; A(3) > 20, CV Therapeutics), that have the potential to provide enhanced insulin sensitivity without cardiovascular side effects or tachyphylaxis. The A(1)-AdoR agonists GW493838 and GR792363 are under evaluation for pain management. The non-nucleosidic A(1)-AdoR agonist, BAY-68-4986 (Capadenoson), represents a unique approach to angina wherein both animal studies and early human studies are promising. The challenges associated with developing an A(1)-AdoR agonist for therapeutic intervention are now well defined in humans. Significant progress has been made in identifying agents for the treatment of atrial arrhythmias, T2D, and angina.
Bioorganic & Medicinal Chemistry Letters, 2008
A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for the... more A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for their affinity for the adenosine receptors (AdoRs). We have discovered two compounds 18 (CVT-7124) and 28 (CVT-6694) that display good affinity for the A 2B AdoR (K i = 6 nM and 7 nM, respectively) and greater selectivity for the human A 1 , A 2A , and A 3 AdoRs (>1000-, >830-, and >1500-fold; >850-, >700-, and >1280-fold, respectively). CVT-6694 has been shown to block the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells (BSMC), a process believed to be promoted by activation of A 2B AdoR.
Bioorganic & Medicinal Chemistry Letters, 2002
Nucleic acids U 0700 Structure-Affinity Relationships of the Affinity of 2-Pyrazolyl Adenosine An... more Nucleic acids U 0700 Structure-Affinity Relationships of the Affinity of 2-Pyrazolyl Adenosine Analogues for the Adenosine A 2A Receptor. -Compounds such as (I) are prepared based on a modelling study. The structure-activity relationships are discussed. -(PALLE*, V. P.; ELZEIN*, E. O.; GOTHE, S. A.; LI, Z.; GAO, Z.; MEYER, S.; BLACKBURN, B.; ZABLOCKI, J. A.; Bioorg. Med. Chem. Lett. 12 (2002) 20,
Bioorganic & Medicinal Chemistry Letters, 2004
Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an e... more Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an estimated 2.3 million cases in the US (2001). A(1) adenosine receptor agonists can slow the electrical impulse propagation through the atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce ventricular rate. Compounds that are full agonists of the A(1) adenosine receptor can cause high grade AV block. Therefore, it is envisioned that a compound that is a partial agonist of the A(1) adenosine receptor could avoid this deleterious effect. 5(') Phenyl sulfides (e.g., 17, EC(50)=1.26 microM) and phenyl ethers (e.g., 28, EC(50)=0.2 microM) are partial agonists with respect to their AV nodal effects in guinea pig isolated hearts. Additional affinity, GTPgammaS binding data suggesting partial activity of the A(1) adenosine receptor, and PK results for 5(') modified adenosine derivatives are shown.
Bioorganic & Medicinal Chemistry Letters, 2004
New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles ... more New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles in the ÔWestern Por-tionÕ of the molecule. SAR studies led to the discovery of CVT-4325 (shown), a potent FOXi (IC 50 = 380 nM rat mitochondria) with favorable PK properties (F = 93%, t 1/2 = 13.6 h, dog).
Bioorganic & Medicinal Chemistry Letters, 2007
A series of new selective, high affinity A(1)-AdoR agonists is reported. Compound 23 that incorpo... more A series of new selective, high affinity A(1)-AdoR agonists is reported. Compound 23 that incorporated a carboxylic acid functionality in the 4-position of the pyrazole ring displayed K(iL) value of 1 nM for the A(1)-AdoR and >5000-fold selectivity over the A(3) and A(2A)-AdoRs. In addition, compound 19 that incorporated a carboxamide functionality in the 4-position of the pyrazole ring displayed subnanomolar affinity for the A(1)-AdoR (K(iL)=0.6 nM) and >600-fold selectivity over the A(3) and A(2A)-AdoRs.
Bioorganic & Medicinal Chemistry Letters, 2004
Bioorganic & Medicinal Chemistry Letters, 2006
A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A 2B ... more A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A 2B -AdoR antagonists have been synthesized and evaluated for their binding affinities for the A 2B , A 1 , A 2A , and A 3 -AdoRs. 8-(1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (K i = 1 nM) and selectivity for the A 2B -AdoR versus A 1 , A 2A , and A 3 -AdoRs (A 1 /A 2B , A 2A /A 2B , and A 3 /A 2B selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.
Nucleosides, Nucleotides and Nucleic Acids, 2001
Compound 20 (CVT-3146--a 2-[(N-1-(4-N-methylcarboxamidopyrazolyl)] adenosine derivative) and comp... more Compound 20 (CVT-3146--a 2-[(N-1-(4-N-methylcarboxamidopyrazolyl)] adenosine derivative) and compound 31 (CVT-3033--a 2-[(4-(1-N-pentylpyrazolyl)] adenosine derivative), were found to be short acting functionally selective coronary vasodilators (CV t0.5 = 5.2 +/- 0.2 and 3.4 +/- 0.5 min, respectively--rat isolated heart 50% reversal time) with good potency (EC50S = 6.4 +/- 1.2 nM and 67.9 +/- 16.7 nM, respectively), but they possess low affinity for the ADO A2A receptor (Ki = 1122 +/- 323 nM and 2138 +/- 952 nM, respectively; pig striatum).