Dhanapalan Nagarathnam
Purdue University
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Journal of Medicinal Chemistry | 1998
Dhanapalan Nagarathnam; John M. Wetzel; Shou Wu Miao; Mohammad R. Marzabadi; George Chiu; Wai C. Wong; Xingfang Hong; James Fang; Carlos Forray; Theresa Branchek; William E. Heydorn; Raymond S. L. Chang; Theodore P. Broten; Charles Gluchowski
We report the synthesis and evaluation of novel α1a adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent α1a antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (−) [(−)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a Ki of 2.8 nM, in agreement with the cloned human receptor binding data (Ki = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a Ki of 3.6 nM and confirmed it to be a potent antagonist (Kb = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP Kb/IUP Kb ratio of 16. In addition, (−)-63 ...
Tetrahedron | 1991
Dhanapalan Nagarathnam; Mark Cushman
Abstract A facile synthetic method has been developed for the conversion of methyl salicylate (5) into flavones 1a-i in high yields. Compound 5 on treatment with t-butyldimethylsilyl chloride (6) gave the O-silyl protected ester 7. Condensation of this ester 7 with the lithium anion generated from acetophenones 3a-i yielded the 1.3-diarylpropane-1,3-diones 8a-i, which on treatment with glacial acetic acid containing 0.5% H2SO4 for 3 h at 95-100 °C provided the desired flavones 1a-i in 83–94% yields.
Tetrahedron Letters | 1990
Mark Cushman; Dhanapalan Nagarathnam
Abstract A general method for the facile synthesis of ring-A hydroxylated flavones is described. Treatment of the hydroxylated acetophenones 6a–d with enough lithium bis(trimethyl)silyl amide to deprotonate all of the phenols as well as to generate the lithium enolate of the ketone, followed by addition of the acid chlorides 7a–d, gave the 1,3-diketones 8a–g, which were cyclized to the desired products 9a–g in high yield.
European Journal of Pharmacology | 1998
Stacey O'Malley; Tsing Bao Chen; Barbara Francis; Raymond E. Gibson; H. Donald Burns; Jerry DiSalvo; Marvin L. Bayne; John M. Wetzel; Dhanapalan Nagarathnam; Mohammad R. Marzabadi; Charles Gluchowski; Raymond S.L. Chang
L-762,459 ((+/-)1-(3-¿[5-carbamoyl-2-2-[(4-hydroxy-3-iodobenzimidoyl)-amino] -ethoxy-methy¿-6-methyl-4-(4-nitropheny)-1,4-dihydropyridine -3-carbonyl]-amino¿-propyl)-4-phenyl-1-piperidine-4-carboxylic acid methyl ester), an analog of a series of dihydropyridines previously reported to be selective alpha1A-adrenoceptor subtype antagonists was found to have alpha1A-adrenoceptor subtype selectivity (Ki (nM), la = 1.3, lb = 240, Id = 280). Specific [125I]L-762,459 binding was detected in rat cerebral cortex, hippocampus, vas deferens, kidney, heart and prostate tissues known to contain the alpha1A-adrenoceptor subtype, but not in tissues known to contain alpha1B-adrenoceptor (spleen, liver) and alpha1D-adrenoceptor (aorta). Scatchard analysis of [125I]L-762,459 binding in rat cerebral cortex and prostate indicated a single binding site with a Kd of 0.7 nM and Bmax of 11 (cerebral cortex) and 1 (prostate) pmole/g tissue. Specific and saturable [125I]L-762,459 binding was also found in human cerebral cortex, liver, prostate and vas deferens (Kd = 0.2-0.4 nM, Bmax = 0.4-4 pmole/g tissue). The specific binding in rat and human tissues was competed by non-selective alpha1-adrenoceptor compounds (Ki values in nM: prazosin (0.14-1.2), terazosin (1.8-5.9) and phentolamine (2.4-11)) and selective alpha1A-adrenoceptor compounds [Ki values in nM: (+) niguldipine (0.04-1.2) and SNAP 5399 ((+/-)-2-((2-aminoethyl)oxy)methyl-5-carboxamido-6-ethyl-4-(4-nitropheny l)-3-N-(3-(4,4-diphenylpiperidin-1-yl)propyl)carboxamido-1,4-dihyd ropyridine hydrate (0.5-4.8)]. The results were consistent with the selective binding of [125I]L-762,459 to the alpha1A-adrenoceptor. The specific labeling of the alpha1A-adrenoceptor subtype by [125I]L-762,459 may make it a useful tool to localize the distribution of the alpha1A-adrenoceptor.
Bioorganic & Medicinal Chemistry Letters | 1991
Mark Cushman; Dhanapalan Nagarathnam; D. Gopal; Robert L. Geahlen
Abstract A series of pyridine-containing stilbene and amide derivatives based on the structure of piceatamol, a naturally occurring protein-tyrosine kinase inhibitor, has been prepared and tested for inhibition of p56lck. The most potent of these compounds is a competitive inhibitor of p56lck with respect to ATP.
Journal of Medicinal Chemistry | 1999
Bharat Lagu; Dake Tian; Dhanapalan Nagarathnam; Mohammad R. Marzabadi; Wai C. Wong; Shou W. Miao; Fengqi Zhang; Wanying Sun; George Chiu; James Fang; Carlos Forray; Raymond S. L. Chang; Richard W. Ransom; Tsing B. Chen; Stacey O'Malley; Kanyin Zhang; Kamlesh P. Vyas; Charles Gluchowski
Dihydropyrimidinones, such as 1, represent a novel class of alpha(1a) adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the mu-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the mu-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the mu-opioid receptor.
Bioorganic & Medicinal Chemistry Letters | 1991
Mark Cushman; Dhanapalan Nagarathnam; D. Gopal; Robert L. Geahlen
Abstract A series of 33 phenylhydrazone derivatives of polyhydroxylated benzaldehydes has been prepared and tested for inhibition of the protein-tyrosine kinase p56lck. The most potent of these compounds was a competitive inhibitor of p56lck with respect to a tyrosine-containing peptide substrate and was similar in potency to piceatannol, a naturally occurring protein-tyrosine kinase inhibitor.
Journal of Medicinal Chemistry | 1991
Mark Cushman; Dhanapalan Nagarathnam; D. Gopal; Asit K. Chakraborti; Chii M. Lin; Ernest Hamel
Journal of Medicinal Chemistry | 1992
Mark Cushman; Dhanapalan Nagarathnam; D. Gopal; Hu Ming He; Chii M. Lin; Ernest Hamel
Journal of Medicinal Chemistry | 1991
Mark Cushman; Dhanapalan Nagarathnam; Debra L. Burg; Robert L. Geahlen