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Biomedical subjects

H W Hamilton

Publications and source records attributed to H W Hamilton.

At least 19 recordsLinked to original sources
PubMed1999

Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor.

With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of > 1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation.

Cell Line↗
PubMed1997

4-hydroxy-5,6-dihydropyrones. 2. Potent non-peptide inhibitors of HIV protease.

The 4-hydroxy-5,6-dihydropyrone template was utilized as a flexible scaffolding from which to build potent active site inhibitors of HIV protease. Dihydropyrone 1c (5,6-dihydro-4-hydroxy-6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one) was modeled in the active site of HIV protease utilizing a similar binding mode found for the previously reported 4-hydroxybenzopyran-2-ones. Our model led us to pursue the synthesis of 6,6-disubstituted dihydropyrones with the aim of filling S1 and S2 and thereby increasing the potency of the parent dihydropyrone 1c which did not fill S2. Toward this end we attached various hydrophobic and hydrophilic side chains at the 6-position of the dihydropyrone to mimic the natural and unnatural amino acids known to be effective substrates at P2 and P2'. Parent dihydropyrone 1c (IC50 = 2100 nM) was elaborated into compounds with greater than a 100-fold increase in potency [18c, IC50 = 5 nM, 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[2-phenylethyl)thio] -2H-pyran-2-yl)pentanoic acid and 12c, IC50 = 51 nM, 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3- [(2-phenyl-ethyl)thio]-2H-pyran-2-one]. Optimization of the 3-position fragment to fill S1' and S2' afforded potent HIV protease inhibitor 49 [IC50 = 10 nM, 3-[(2-tert-butyl-5-methylphenyl)sulfanyl]-5,6-dihydro-4 -hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one]. The resulting low molecular weight compounds (< 475) have one or no chiral centers and are readily synthesized.

Anti-HIV Agents↗
PubMed1995

Design and synthesis of renin inhibitors: incorporation of transition-state isostere side chains that span from the S1 to the S3 binding pockets and examination of P3-modified renin inhibitors.

A series of renin inhibitors were designed to examine the topography of the contiguous binding pocket of renin that is normally occupied by the P1 and P3 side chains. Molecular modeling suggested that extending the P1 hydrophobic side chain into the adjacent hydrophobic S3 enzyme pocket was feasible. Novel transition state isosteres with modified P1-->P3 side chains were synthesized and provided enhanced binding affinity when incorporated into renin inhibitors in which the P3 Phe was substituted by Gly. In a complementary approach, the binding affinities of a variety of P3-P4-modified peptidomimetic renin inhibitors that lacked substantial hydrophobic side chains at these sites were measured.

Amides↗
PubMed1995

Evaluation of physicochemical parameters important to the oral bioavailability of peptide-like compounds: implications for the synthesis of renin inhibitors.

A series of radiolabeled compounds related to renin inhibitor structures was synthesized to represent a range of physicochemical properties. These compounds were tested in assays for intestinal absorption and hepatic clearance in order to define parameters conducive to optimizing bioavailability. In general, compounds with higher lipophilicity were better absorbed from the intestine. Absorption may also be dependent on molecular charge, as compounds with ionizable functionality were less well-absorbed than neutral compounds. Neutral compounds showed some dependency on molecular weight, with smaller compounds exhibiting better absorption. While uptake into hepatic cells was rapid regardless of partition coefficient or molecular weight, rate of appearance in bile was dependent on the molecular weight of the compounds.

Administration, Oral↗
PubMed1995

Comparison of intestinal permeabilities determined in multiple in vitro and in situ models: relationship to absorption in humans.

In vitro and in situ experimental models that are descriptive of drug absorption in vivo are valuable tools in the discovery of new chemical entities that are bioavailable after oral administration. The specific objective of the study was to compare the intestinal permeabilities obtained in the three absorption models for consistency, and to assess the utility of the models in predicting the fraction of dose absorbed in human studies. The intestinal absorption models that were compared are widely used: the rat in situ single-pass intestinal perfusion system, the rat everted intestinal ring method, and monolayers of human colon adenocarcinoma cell line (CACO-2). The models were compared using small molecular reference compounds, as well as a series of peptidomimetic (PM) analogs. Each model had strong potential for estimating the fraction absorbed. For small organic molecules, excellent correlation was observed when permeabilities from CACO-2 cells and perfusions, or everted rings and perfusions, were compared. Weaker correlation was observed between everted rings and CACO-2 cells. Permeabilities for the set of reference compounds and PMs were positively correlated between any two of the three systems. Variance between correlations for reference compounds and PMs are likely due to structural features and physicochemical properties that are unique to the latter class of compounds. The results support caution in extrapolating correlations based on findings with small organic molecules to the behavior of complex peptidomimetics. Corroboration of permeabilities with two methods of determination is a useful cross-validation of experimental systems, as well as producing a reliable permeability assessment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1995

Low friction arthroplasty at 10 to 20 years. Consequences of plastic wear.

One hundred eighty-seven patients, in whom 224 low friction arthroplasties were done by 1 surgeon from 1972 to 1983, were observed for 10 to 20 years. An attempt was made to reassess each patient annually. Pain, walking, and passive range of motion were graded on a 6-point scale (d'Aubigné and Postel assessment). Active movements, straight leg raising, and abduction against gravity were recorded in degrees. The average scores, based on 224 assessments done preoperatively, 1914 assessments done during the first 10 years, and 590 assessments done during the second 10 years, were as follows: pain--3.28, 5.71, and 5.59 points; walking--3.34, 5.16, and 4.87 points; passive range of motion--3.42, 4.61, and 4.54 points; straight leg raising--40.5 degrees, 60.8 degrees, and 54.9 degrees points; and abduction against gravity--8.8 degrees, 24.3 degrees, and 19.0 degrees points. The percentage of cases with no cement-bone interface demarcation based on > 2000 radiologic observations was as follows: cup Zone I--9.9%, Zone II--26.4%, and Zone III--26.3%; and femoral Zone 1--72.5%, Zone 2--96.7%, Zone 3--94.2%, Zone 4--89.6%, Zone 5--96.7%, Zone 6--96.3%, and Zone 7-72.6%. A relationship was seen between wear of the socket, and cup migration and revision, development of femoral endosteal erosions (significant at 95% confidence level), and femoral prosthesis migration and revision. Ultra high molecular weight polyethylene particles that migrate to the cement-bone interface are believed to be an important cause of loosening and failure in total hip arthroplasty.

Female↗
PubMed1993

Analyses of ligand binding in five endothiapepsin crystal complexes and their use in the design and evaluation of novel renin inhibitors.

Five renin inhibitors were cocrystallized with endothiapepsin, a fungal enzyme homologous to renin. Crystal structures of inhibitor-bound complexes have provided invaluable insight regarding the three-dimensional structure of the aspartic proteinase family of enzymes, as well as the steric and polar interactions that occur between the proteins and the bound ligands. Beyond this, subtleties of binding have been revealed, including multiple subsite binding modes and subsite interdependencies. This information has been applied in the design of novel potent renin inhibitors and in the understanding of structure-activity relationships and enzyme selectivities.

Amino Acid Sequence↗
PubMed1992

Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors.

A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.

Animals↗
PubMed1991

N6-substituted adenosine receptor agonists: potential antihypertensive agents.

Adenosine is known to exert a wide range of pharmacological effects including hypotension. This effect of adenosine suggested that modified analogues of adenosine might provide useful antihypertensive agents. Thus, we prepared a series of novel N6-benzocycloalkyladenosines and studied their receptor binding and antihypertensive activity. The structure-activity relationship study shows that the adenosine analogues having the hydrophobic phenyl moiety one carbon away from the C6-nitrogen have modest affinity and selectivity for the A1 receptor, whereas those with the phenyl moiety two carbons away from the C6-nitrogen have excellent affinity and selectivity for the A1 receptor. Many of these analogues showed excellent antihypertensive activity with a wide range of effects on heart rate. There is no direct correlation between the receptor binding affinities and antihypertensive activity; however, it is more closely associated with A1 than A2 affinity. The bradycardic effect of these agonists seems to be due to the A1 affinity. From this set, compound 3 was further evaluated in secondary antihypertensive screens. It lowered the blood pressure dose dependently with effects lasting for over 20 h following administration of a 30 mg/kg dose. Compound 3 was also effective in lowering blood pressure in a renal hypertensive rat model. Thus, appropriately modified N6-substituted adenosines represent a novel class of antihypertensive agents.

Adenosine↗
PubMed1988

Computer corner #18. A computer program suitable for routine hip replacement follow up and clinical research.

A computer program was developed to facilitate routine follow up examination of patients with total hip replacements and to allow detailed analysis of the collected data for clinical research purposes. Information on more than 800 low friction arthroplasties has now been entered into the computer program. The system is versatile and can be modified to suit particular needs. The method of entering and recalling data can be learned rapidly by those unfamiliar with computers, however, analysis of the data requires advanced computer expertise. Hardware and software requirements for the program are listed at the end of this article.

Follow-Up Studies↗
PubMed1988

Shrinkage of centrifuged cement.

Two postulated mechanisms for the failure of prosthetic implants secured with bone cement are: failure of the cement itself, and loosening at the bone/cement interface. Failure rate with cement can be reduced by increasing the strength of the cement, and loosening can be reduced by minimizing cement shrinkage during polymerization. This paper shows that centrifuging cement to reduce porosity (and presumably increase strength) results in a substantial increase in cement shrinkage over uncentrifuged cement. A second set of experiments demonstrated that pressurization of cement to four atmospheres during polymerization resulted in tensile strengths comparable with those reported for centrifuged cement. Thus, the use of uncentrifuged bone cement, pressurized during polymerization, should minimize implant failure rates.

Atmospheric Pressure↗
PubMed1987

Correlation of adenosine receptor affinities and cardiovascular activity.

Binding affinities of 28 adenosine analogs at A1 adenosine receptors (rat whole brain membranes, [3H]N6-cyclohexyladenosine, CHA), and at A2 adenosine receptors (rat striatal membranes, [3H]NECA) were compared to their EC25 values for decreasing heart rate and increasing coronary flow in the isolated rat heart. Heart rate (an A1 response) correlated with A1 binding affinity (r2 = 0.71, p less than 0.0001) but not with A2 binding affinity (r2 = 0.007, n.s.); conversely, coronary flow (an A2 response) correlated with A2 binding affinity (r2 = 0.83, p less than 0.0001) but not with A1 binding affinity (r2 = 0.05, n.s.). These results confirm that the brain A1 and A2 receptors, studied by binding methods, bear close similarities to their respective counterparts in the heart, studied by means of functional responses.

Adenosine↗
PubMed1987

PD 116,948, a highly selective A1 adenosine receptor antagonist.

(R)-N-(1-Methyl-2-phenylethyl) adenosine (R-PIA), an adenosine receptor agonist has both negative chronotropic activity and coronary vasodilator activity. These actions of R-PIA are proposed to be mediated by subtypes (A1 and A2) of adenosine receptors. PD 116,948 is a xanthine derivative which is a highly selective A1 adenosine receptor ligand. In this study PD 116,948 selectively antagonized the negative chronotropic activity of R-PIA in the isolated rat heart. These results are consistent with, and add further support to the hypothesis that adenosine receptor agonists mediate their negative chronotropic activity via A1 receptors and their vasodilator activity via A2 receptors.

Adenosine↗
PubMed1987

Synthesis and structure-activity relationships of pyrazolo[4,3-d]pyrimidin-7-ones as adenosine receptor antagonists.

A series of 21 1,3-dialkylpyrazolo[4,3-d]pyrimidin-7-ones substituted in the 5-position with various phenyl substituents has been synthesized and found to have affinity for the adenosine A1 receptor. The potency pattern due to substituents of the phenyl ring was found to parallel that found in a previously reported 1,3-dialkyl-8-phenylxanthine series. A quantitative structure-activity relationship was developed between these two series that correctly predicted the potencies of six additional 5-substituted pyrazolo[4,3-d]pyrimidines that were synthesized during the course of the analysis. With use of the correlation as a guide, one additional 5-phenylpyrazolo[4,3-d]pyrimidine containing a 4-[[(dimethylamino)ethyl]amino]sulfonyl substituent to improve aqueous solubility was prepared. On the basis of the high correlation between adenosine binding affinities of analogously substituted xanthines and pyrazolo-[4,3-d]pyrimidines and the close superposition of the heterocyclic rings and substituents that is apparent from molecular models of these two series, it is hypothesized they fit the receptor in an analogous fashion.

Adenosine↗
PubMed1986

Ribose-modified adenosine analogues as adenosine receptor agonists.

Analogues of the potent adenosine receptor agonist (R)-N-(1-methyl-2-phenylethyl)adenosine (R-PIA), modified at N9, were prepared and evaluated for adenosine A1 and A2 receptor binding and in vivo central nervous system and cardiovascular effects. The modifications at N9 include deoxy sugars, 5'-substituted-5'-deoxyriboses, non-ribose sugars, sugar ring homologues, and acyclic sugar analogues. Most of the derivatives have poor affinity for adenosine receptors. Only minor modifications at C5' and C3' maintain potent binding. In general, those derivatives exhibiting in vivo behavioral or cardiovascular effects also have the highest affinity for adenosine receptors.

Adenosine↗