Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.

Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.

In utero progression of isolated renal pelvis dilation.

The objective of this study to determine the risk of in uteroprogression of renal pelvis dilation when detected on antenatal ultrasound examination. We reviewed 230 fetuses with evidence of renal pelvis dilation. At least one exam was subsequently performed prior to delivery in all cases. Renal pelvis dilation was defined as an anterior-posterior renal pelvis measurement > 4 mm at < 32 weeks' and > 7 mm at > or = 32 weeks' gestation. Hydronephrosis was considered to be present when the renal pelvis measured +10 mm independent of gestational age. Multiple gestations and fetuses with additional congenital anomalies were excluded. The mean gestational age at diagnosis was 24 weeks. Renal pelvis dilation progressed to hydronephrosis in a total of 10.9% (25 of 230) of fetuses. There was a 3.3% chance of unilateral renal pelvis dilation progressing to hydronephrosis versus 26.0% in bilateral dilation (OR 10.4 [95% Cl 3.5-33.3]). Of those fetuses with progression, 80% had bilateral dilation (p < 0.0001). There was no difference in progression between right and left kidneys. Additionally, gender, gestational age at diagnosis and delivery, and birth weight did not differ between those fetuses with and without progression. The hydronephrosis in 7 of 25 (28%) regressed to pyelectasis on a subsequent ultrasound exam. Thus, the overall rate of progression of renal pelvis dilation to persistent hydronephrosis was 7.8% (18 of 230). In conclusion, the risk of isolated renal pelvis dilation progressing to hydronephrosis is low. Although bilateral pelvis dilation carries a higher risk for progression, no fetus in our study required in utero intervention. A follow up scan prior to delivery may be considered to identify those fetuses who will require postpartum intervention.

A priori prediction of activity for HIV-1 protease inhibitors employing energy minimization in the active site.

We have observed a high correlation between the intermolecular interaction energy (Einter) calculated for HIV-1 protease inhibitor complexes and the observed in vitro enzyme inhibition. A training set of 33 inhibitors containing modifications in the P1' and P2' positions was used to develop a regression equation which relates Einter and pIC50. This correlation was subsequently employed to successfully predict the activity of proposed HIV-1 protease inhibitors in advance of synthesis in a structure-based design program. This included a precursor, 47, to the current phase II clinical candidate, L-735,524 (51). The development of the correlation, its applications, and its limitations are discussed, and the force field (MM2X) and host molecular mechanics program (OPTIMOL) used in this work are described.

L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor.

A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with Ki values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1IIIb-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.

Synthesis, antiviral activity, and bioavailability studies of gamma-lactam derived HIV protease inhibitors.

Incorporation of a gamma-lactam in hydroxyethylene isosteres results in modest inhibitors of HIV-1 protease. Additional structural activity studies have produced significantly more potent inhibitors with the introduction of the trisubstituted cyclopentane (see compound 20) as the optimum substituent for the C-terminus. This new amino acid amide surrogate can be readily prepared in large scale from (R)-pulegone. Optimized compounds (36) and (60) are potent antiviral agents and are well absorbed (15-20%) in a dog model after oral administration.

L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor.

To date, numerous inhibitors of the human immunodeficiency virus type 1 protease have been reported, but few have been studied extensively in humans, primarily as a consequence of poor oral bioavailability in animal models. L-735,524 represents a class of human immunodeficiency virus type 1 protease inhibitors, termed hydroxyaminopentane amides, that incorporate a basic amine into the hydroxyethylene inhibitor backbone. L-735,524 is a potent inhibitor of virus replication in cell culture and inhibits the protease-mediated cleavage of the viral precursor polyproteins that results in the production of noninfectious progeny viral particles. The compound is effective against viruses resistant to reverse transcriptase inhibitors and is synergistically active when used in combination with reverse transcriptase inhibitors. Most importantly, L-735,524 exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals by using clinically acceptable formulations. Accordingly, the compound was selected for evaluation of safety and pharmacokinetic studies in humans.

Synthesis and evaluation of 2-pyridinone derivatives as HIV-1 specific reverse transcriptase inhibitors. 1. Phthalimidoalkyl and -alkylamino analogues.

A potent (IC50 = 30 nM), specific nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor 3-[N-(phthalimidomethyl)amino]-5-ethyl-6-methylpyridin-2(1H) -one (1), was discovered through an in vitro screening program. This compound did not inhibit (IC50 > 300 microns) other DNA and RNA polymerases, including HIV-2 RT and SIV-RT. Unfortunately, hydrolytic instability of this (aminomethyl)phthalimide precluded use as an antiviral agent. In the first paper of this series, preliminary development efforts are described which produced ethylphthalimide 20, a hydrolytically stable compound with reduced (100-fold) HIV-1 RT inhibitory activity and weak (CIC95 = 40 microM) antiviral activity in H9 cells. Structure-activity studies demonstrated the importance of the 5-ethyl, 6-methyl substituent pattern on the pyridinone ring and the need for a flexible two-atom linker between the pyridinone and phthalimide heterocycles. These leads, 1 and 20, provided a basis for the further development of this structural class of inhibitors from which several compounds, the subject of accompanying reports, were selected for clinical evaluation.

Self-reported depression profiles in chronic pain and family practice patients.

This study examined profiles of self-reported depressive symptoms in chronic pain patients (n = 51), family practice outpatients (n = 52), and controls (n = 53) who were receiving neither psychological nor medical treatment and were pain free. Subjects in the three groups were matched for age and sex. The short form of the Multiscore Depression Inventory (SMDI) was used. Chronic pain and family practice groups had similar SMDI profiles, with significant elevations on Low Energy, Pessimism, Sad Mood, and Low Self-Esteem subscales compared with controls. Although both groups of medical patients were depressed compared with control subjects, their SMDI profiles were different from those previously reported for psychiatric inpatients with a diagnosis of depression.

Chronic pain: its treatment in geriatric and younger patients.

The response of geriatric patients to a multidisciplinary chronic pain rehabilitation program was measured by comparing outcome data on 17 older patients (55 to 78 years) to data on 20 younger patients (29 to 48 years) treated in the same program. Pretreatment data were obtained at an initial evaluation, and posttreatment data were obtained at the most recent follow-up contact, usually at 12 months after treatment. Treatment outcome was assessed on the basis of eight quantitative measures: pain ratings; health care utilization; activity tolerance; daily "up time"; hours per week spent in paid employment, housework, volunteer work, or school; medication intake; SCL-90R somatization, depression, and anxiety scores; and an overall summary measure. Pretreatment data indicated that older and younger groups were similar on both demographic variables and clinical status. There was a larger percentage of women in the older group. The older patients were initially somewhat more impaired than the younger ones, with nearly four times the rate of health care utilization and almost two times higher medication intake. Both groups improved significantly from pretreatment to posttreatment on most of the eight measures. Older patients showed a greater decrease in health care utilization. Women and men did not respond differentially to treatment. The data indicated that geriatric patients can benefit from chronic pain rehabilitation programs at least as much as, if not more than, younger patients.

Blood glucose discrimination training with insulin-dependent diabetics: a clinical note.

Two insulin-dependent diabetic adults were exposed to a blood glucose discrimination training program. Following baseline, during which subjects estimated their blood glucose levels twice daily, subjects received immediate feedback regarding the accuracy of their estimates. The procedure resulted in a large increase in accuracy of blood glucose level estimation. The implications of the findings were discussed.