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Biomedical subjects

R N Misra

Publications and source records attributed to R N Misra.

At least 19 recordsLinked to original sources
PubMed2000

Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: synthesis and biological effects.

Flavopiridol analogues, thio- and oxoflavopiridols which contain a sulfur (16) or oxygen (18) atom linker between a chromone ring and the hydrophobic side chain, are selective cyclin-dependent kinase 1 (CDK1) inhibitors with an IC(50) of 110 and 130 nM. These analogues were prepared from key intermediate 7 by substituting the ethyl sulfoxide. Enantio pure intermediate piperidone 10 was obtained from the racemic piperidone 8 via a very efficient "dynamic kinetic resolution" in 76% yield. Hydrophobic side chains such as chlorophenyl or tert-butyl produced potent CDK1 inhibitory activity, while hydrophilic side chains such as pyrimidine or aniline caused a severe reduction in CDK inhibitory activity. These analogues are competitive inhibitors with respect to ATP, and therefore activity was dependent upon the CDK subunit without being affected by the cyclin subunit or protein substrate. Thio- and oxoflavopiridols 16 and 18 are not only selective within the CDK family but also discriminated between unrelated serine/threonine and tyrosine protein kinases. CDK1 selective thio- and oxoflavopiridol analogues inhibit the colony-forming ability of multiple human tumor cell lines and possess a unique antiproliferative profile in comparison to flavopiridol.

Antineoplastic Agents↗
PubMed1999

Cardioselective antiischemic ATP-sensitive potassium channel (K(ATP)) openers. 6. Effect of modifications at C6 of benzopyranyl cyanoguanidines.

The effect on potency and selectivity of modifications at the C6 position of the cardioprotective K(ATP) opener BMS-180448 (2) is described. Structure-activity studies show that a variety of electron-withdrawing groups (ketone, sulfone, sulfonamide, etc.) are tolerated for cardioprotective activity as measured by EC(25) values for an increase in time to the onset of contracture in globally ischemic rat hearts. Changes made to the sulfonamido substituent indicate that compounds derived from secondary lipophilic amines are preferred for good cardioprotective potency and selectivity. The diisobutyl analogue 27 (EC(25) = 0.04 microM) is the most potent compound of this series. The cardiac selectivity of 27 results from a combination of reduced vasorelaxant potency and enhanced cardioprotective potency relative to the potent vasodilating K(ATP) openers (e.g., cromakalim). The diisobutylsulfonamide analogue 27 is over 4 orders of magnitude more cardiac selective than cromakalim (1). These results support the hypothesis that the cardioprotective and vasorelaxant properties of K(ATP) openers follow distinct structure-activity relationships. The mechanism of action of 27 appears to involve opening of the cardiac K(ATP) as its cardioprotective effects are abolished by the K(ATP) blocker glyburide.

Animals↗
PubMed1998

Biphenylsulfonamide endothelin antagonists: structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1, 1'-biphenyl]-2-sulfonamide (BMS-187308).

Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.

Administration, Oral↗
PubMed1997

Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase.

A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Management of giardiasis by a herbal drug 'Pippali Rasayana': a clinical study.

Pippali Rasayana (PR), an Indian ayurvedic drug prepared from Palash (Butea monosperma (Lamk) Kuntze; Leguminaceae) and Pippali (Piper longum L.; Piperaceae), was administered at a dose of 1 g p.o. three times daily for a period of 15 days to patients (25 treated, 25 placebo controls) suffering from giardiasis with clinical signs and symptoms, and stools positive for trophozoites/cysts of Giardia lamblia. After 15 days of drug treatment there was a complete disappearance of G. lamblia (trophozoites/cysts) from the stools of 23 out of 25 patients. General signs and symptoms of ill health and abdominal discomfort, presence of mucus, pus cells and RBCs were significantly reduced. There was a marked improvement in the clinical and haematological profile of the patients. Spontaneous recovery in 20% cases was recorded in placebo controls.

Adjuvants, Immunologic↗
PubMed1996

Pattern of gastric emptying in patients with systemic sclerosis.

Gastric emptying studies, using an indigenously prepared radiolabeled solid food marker in the form of Indian bread called Chapati, were performed on 13 patients with systemic sclerosis. Six patients had limited cutaneous disease and seven had diffuse cutaneous disease. Earlier, the procedure was standardized in 30 healthy volunteers. Seven of the 13 (54%) patients (five with diffuse and two with limited cutaneous disease) had delayed gastric emptying. Most of these patients had gastric symptoms. This pattern of gastric emptying may be clinically significant, particularly in patients with diffuse cutaneous disease.

Adult↗
PubMed1995

Magnetic resonance appearance of tuberculosis of the knee joint with ruptured Baker's cyst.

After the spine, the knee joint is the most commonly affected joint in skeletal tuberculosis. Baker's cyst is a rather rare complication of knee joint tuberculosis. The plain radiographic appearance of the tuberculous knee joint has been amply described. We present the magnetic resonance appearance of a tuberculous knee joint associated with a ruptured popliteal cyst.

Biopsy, Needle↗
PubMed1993

Interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles. Highly potent, selective, and long-acting thromboxane A2 receptor antagonists.

A series of interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles (2) were prepared and evaluated for their thromboxane (TxA2) antagonistic activity in vitro and duration of action in vivo. Examination of the carboxyl side chain indicated that the interphenylene ring substitution pattern and, to a lesser extent, chain length were important factors in determining TxA2 antagonistic potency. For the carboxyl side chain, ortho substitution, a single methylene spacer between the interphenylene and oxabicycloheptane rings, and a propionic acid side-chain length were determined to be optimal. With respect to the oxazole side chain a wide range of amide substituents with diverse structures and lipophilicities were compatible with potent antagonistic activity. Finally, an acidic functional group on the alpha-chain and a hydrogen bond acceptor on the 4-position of the oxazole ring were critical for potent activity. From the analogs prepared 42 (BMS-180,291: [(+)-1S-(1 alpha, 2 alpha, 3 alpha, 4 alpha)-2-[[3-[4-[(n- pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2- yl]methyl]benzenepropanoic acid) was found to be a potent, selective, and orally-active TxA2 antagonist with a long duration of action and has been selected as a candidate for clinical development. In human platelet-rich plasma, 42 inhibited arachidonic acid (800 microM) and U-46,-619 (10 microM) induced aggregation with I50 values of 7 and 21 nM, respectively. Radioligand binding studies of 42 with [3H]-SQ 29,548 showed a Kd value of 4.0 +/- 1.0 nM in human platelet membranes. Both in vitro and in vivo studies indicated 42 was devoid of direct agonistic activity. In vivo 42 (0.2 mg/kg, po) showed extended protection (T50 = 14.4 h) from U-46,619 (2 mg/kg, iv) induced death in mice, and a single oral dose of 42 (3 mg/kg) abolished U46,619-induced platelet aggregation ex vivo in African green monkeys for > 24 h.

Animals↗
PubMed1993

Pharmacological profile of BMS 180,291: a potent, long-acting, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist.

180,291 1S-(1 alpha, 2 alpha, 3 alpha, 4 alpha)-2-[[3-[4- [(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept- 2- yl]methyl]benzenepropanoic acid (BMS) is a potent and highly selective antagonist of thromboxane A2/prostaglandin endoperoxide (TP) receptors. In human platelet-rich plasma, BMS 180,291 inhibited platelet aggregation induced by arachidonate (800 microM) and U-46,619 (10 microM) with respective IC50 values of 7 +/- 1 (S.E.M.) and 21 +/- 2 nM. Inhibition of both the rate and full extent of 11,9-epoxymethano-prostaglandin H2 (U-46,619)-induced platelet aggregation were insurmountable at antagonist concentrations > 10 nM, but BMS 180,291 antagonized U-46,619-induced platelet shape change competitively with a KB of 11 +/- 2 nM. BMS 180,291 concentrations < or = 1 mM did not inhibit platelet aggregation induced by high concentrations of ADP (20 microM) or human alpha-thrombin (1 U/ml). BMS 180,291 inhibited binding of [3H]1S-[1 alpha,2 alpha(5Z),3 alpha,4 alpha]-7-[3-[[2- [(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]-hept-2- yl]-5-heptenoic acid to human platelet membranes with a kd of 4.0 +/- 1.0 nM and slope factor of 1.06 +/- 0.13. U-46,619-induced concentrations of rat aortae were competitively antagonized by BMS 180,291 with a KB of 0.6 +/- 0.1 nM. Aortic responses to norepinephrine, serotonin and angiotensin II were not inhibited by BMS 180,291 at 1 microM. U-46,619-induced contractions of guinea pig tracheal rings were antagonized in an almost all-or-none manner, with maximal blockade at > or = 1 nM BMS 180,291, but little effect at lower concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Binding and function of a potent new thromboxane receptor antagonist, BMS 180,291, in human platelets.

Binding and function of BMS 180,291 ([(+)1S-(1 alpha,2 alpha,3 alpha,4 alpha)]-2-[[3-[4-[(n-pentylamino)carbonyl]-2-oxazolyl]-7- oxabicyclo[2.2.1] hept-2-yl]methyl]benzenepropanoic acid]) in human platelets was examined. Kinetic determination of [3H]BMS 180,291 binding produced ligand-receptor association and dissociation rates of 1.4 x 10(7) +/- 0.2 M-1 x min-1 (n = 5) and 0.04 +/- 0.005 min-1 (n = 5), respectively. The resultant Kd was 3.1 +/- 1.1 nM (n = 5). Saturation binding analysis in platelet membranes was consistent with a single class of [3H]BMS 180,291 binding sites with a Kd of 3.6 +/- 0.19 nM (n = 4) and a binding site maxima (Bmax) of 2099.1 +/- 70.3 fmol/mg of protein (n = 4). Specific [3H]BMS 180,291 binding was inhibited by thromboxane A2/endoperoxide receptor antagonists and agonists with a rank order of potency of: BMS 180,291 > or = SQ 29,548 = I-BOP race 15-(1 alpha,2 beta(5Z), 3 alpha(1E,3S),4 alpha) d7-[3-(3-hydroxy-4-(p-iodophenoxy)-1-butenyl)-7- oxabicyclo[2.2.1]hept-2-yl]5-heptenoic acid) > or = BM 13,505 > or = SQ 30,741 = U 44,609 > U 46,619 >> BM 13,177. Prostaglandin E2 and prostacyclin did not appreciably inhibit the specific binding of [3H]BMS 180,291. BMS 180,291 (10 nM-5 microM) shifted the I-BOP-induced platelet shape change curve to the right in a parallel manner without reduction of the maximal response (KB = 13 +/- 3.5 nM; pA2 = 8 +/- 0.2; slope = -1.0 +/- 0.05), whereas 30 nM drug decreased the maximal I-BOP-induced platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Biphenyl Compounds↗
PubMed1991

The effect of paper industry effluent on growth, pigments, carbohydrates and proteins of rice seedlings.

The effect of paper industry effluent on the growth and content of certain macromolecules of seedlings of rice (Oryza sativa L. cv. Kesari-82K) has been examined. The effects were investigated in relation to both concentration of effluent and time of exposure to the effluent. Percentage of germination, water imbibing capacity, growth, pigment, carbohydrate and protein content showed a decreasing trend with increase in effluent concentration and time. Protein content was the most sensitive macromolecule affected by effluent. Measurement of protein and protein enzymes might therefore provide a useful criterion for the evaluation of the phytotoxicity of effluent released from the pulp and paper industries.

Journal Article↗
PubMed1991

Interphenylene 7-oxabicyclo[2.2.1]heptane thromboxane A2 antagonists. Semicarbazone omega-chains.

A series of chiral interphenylene 7-oxabicyclo[2.2.1]heptane semicarbazones 19-26 were prepared and evaluated for their in vitro thromboxane (TxA2) antagonistic activity and in vivo duration of action. The potency of 19-26 was found to highly dependent on the substitution pattern of the interphenylene ring and decreased in the order ortho greater than meta much greater than para. SQ 35,091 (25), [1S-(1 alpha,2 alpha,3 alpha,4 alpha)]-2-[[3-[[[(phenylamino) carbonyl]hydrazono]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl] benzenepropanoic acid, was identified as a potent and long-acting TxA2 antagonist. In human platelet rich plasma SQ 35,091 inhibited arachidonic acid (800 microM) and U-46,619 (10 microM) induced aggregation with I50 values of 3 and 12 nM, respectively. In contrast, no inhibition of ADP (20 microM) induced aggregation was observed at greater than 1000 microM. Receptor binding studies with [3H]-SQ 29,548 showed SQ 35,091 was a competitive antagonist with a Kd value of 1.0 +/- 0.1 nM in human platelet membranes. In vivo SQ 35,091 (0.2 mg/kg po) showed extended protection (T50 = 16 h) from U-46,619 (2 mg/kg iv) induced death in mice. These compounds have for the first time demonstrated that a metabolically stable interphenylene alpha-sidechain can be introduced into a prostanoid-like series of TxA2 antagonists with the maintainance of potent antagonistic activity.

Adenosine Diphosphate↗