Considerations for prostheses choice in multiple valve surgery.

OBJECTIVES: The prosthesis type for multiple valve surgery (replacement of two or more diseased native or prosthetic valves, replacement of two diseased valves with repair/reconstruction of a third, or replacement of a single diseased valve with repair/reconstruction of a second valve) remains inadequately evaluated. The clinical performance of multiple valve surgery with bioprostheses (BP) and mechanical prostheses (MP) was assessed to compare patient survival and composites of valve-related complications. METHODS: Between 1975 and 2000, 1245 patients had multiple valve surgery (BP 785, mean age 62.0 ± 14.7 years; and MP 460, mean age 56.9 ± 12.9 years). There were 1712 procedures performed [BP 969(56.6%) and MP 743(43.4%). Concomitant coronary artery bypass (conCABG) was BP 206(21.3%) and MP 105(14.1%) (p = 0.0002). The cumulative follow-up was BP 5131 years and MP 3364 years. Independent predictors were determined for mortality, valve-related complications and composites of complications. RESULTS: Unadjusted patient survival at 12 years was BP 52.1 ± 2.1% and MP 54.8 ± 4.6% (p = 0.1127), while the age adjusted survival was BP 48.7 ± 2.3% and MP 54.4 ± 5.0%. The predictors of overall mortality were age [Hazard Ratio (HR) 1.051, p < 0.0001], previous valve (HR 1.366, p = 0.028) and conCABG (HR 1.27, p = 0.021). The actual freedom from valve-related mortality at 12 years was BP 85.6 ± 1.6% and MP 91.0 ± 1.6% (actuarial p = 0.0167). The predictors of valve-related mortality were valve type (BP > MP) (2.61, p = 0.001), age (HR 1.032, p = 0.0005) and previous valve (HR 12.61, p < 0.0001). The actual freedom from valve-related reoperation at 12 years was BP 60.8 ± 1.9% and MP85.6 ± 2.1% (actuarial p < 0.001). The predictors of valve-related reoperation were valve type (MP > BP) (HR 0.32, p < 0.0001), age (HR 0.99, p = 0.0001) and previous valve (HR 1.38, p = 0.008) CONCLUSIONS: Overall survival (age adjusted) is differentiated by valve type over 10 and 12 years and valve-related mortality and valve-related reoperation favours the use of mechanical prostheses, overall for multiple valve surgery.

Hydrophilic polymer embolization after thoracic endovascular aortic repair.

Hydrophilic polymer embolization is a rare complication after endovascular procedures that is currently underappreciated. Present understanding on this phenomenon relies on sparse case reports with histologic evidence of foreign polymers in end-organ tissue. Here, we report two deaths associated with hydrophilic polymer embolization after complex thoracic endovascular aortic repair.

Transapical Coil Embolization of a Postsurgical Ascending Thoracic Aortic Pseudoaneurysm.

Ascending aortic pseudoaneurysms are a rare but potentially life-threatening complication of aortic root or cardiac surgery. Surgical repair is established as first-line treatment; however, patient comorbidities, technical considerations, and anatomic limitations often preclude patients from repeat surgery, thus necessitating alternative approaches. Here, we present a case of coil embolization of an ascending aortic pseudoaneurysm via a transapical approach in a particularly complex scenario where percutaneous and peripheral access was technically unfeasible.

Outcomes of a Spinal Drain and Intraoperative Neurophysiologic Monitoring Protocol in Thoracic Endovascular Aortic Repair.

BACKGROUND: Adjuncts for early detection and treatment of spinal cord ischemia (SCI) in thoracic aortic surgery are supported by robust clinical experience in open repair. The utility of cerebrospinal fluid (CSF) drainage and neurophysiologic monitoring (NPM) in thoracic endovascular aortic repair (TEVAR) is less clear. The purpose of this investigation is to determine the influence of a selective institutional spinal cord protection protocol using prophylactic NPM and CSF on outcomes for standard TEVAR. METHODS: Patients undergoing standard TEVAR entered into a prospectively maintained database from a single institution from 2007 to 2016 were retrospectively reviewed. Preoperative characteristics, aneurysm extent, and etiology were reviewed. Utilization of CSF drains including volume of fluid removed, duration of drainage, and catheter-related complications were collected. NPM data were reviewed to determine the influence on intraoperative management. Exact logistic regression was used to identify independent predictors of SCI. RESULTS: Of 223 patients undergoing TEVAR, 130 met inclusion criteria for the study. CSF drains were used in 71 patients (54.6%), and 56 of 130 (43%) had NPM. SCI occurred in 7 patients (5.4%), of whom 5 had partial or complete recovery. Median time to symptoms of SCI was delayed in all cases (median 52 hr, range 8-312), and none of the 4 of 7 patients with adjunct NPM demonstrated intraoperative changes. Intraoperative changes in NPM occurred in 26 (46%), and represented unilateral leg ischemia in all but 2 cases. In both patients, changes consistent with SCI were associated with intraoperative hypotension and resolved with blood pressure augmentation. Neither patient developed postoperative SCI. Median length of stay (22 vs. 9 days, P = 0.012), operative room time (262 vs. 209, P = 0.040), and perioperative mortality (28.6% vs. 4.1%, P = 0.046) were significantly higher for patients with SCI versus those without. Length of aortic coverage was found to be the sole independent predictor of SCI (odds ratio 8.2, P = 0.026). Complications related to CSF drainage occurred in 4 patients (5.6%) with major complications occurring in 2 patients (2.8%), including 1 with an intrathecal hematoma and permanent bilateral paraparesis. CONCLUSIONS: Selective use of prophylactic CSF drainage in TEVAR was associated with moderate risk and questionable benefit. The use of neurophysiological monitoring allowed for early detection and treatment of spinal ischemia, but its utility is limited by logistical factors and to the minority of patients with intraoperative spinal ischemic events.

Combined CT, Fluoroscopic and IVUS Guidance for Percutaneous Treatment of a Postsurgical Pseudoaneurysm Following Repair of Ascending Thoracic Aortic Aneurysm.

Thoracic aortic pseudoaneurysms are a recognized complication following aortic arch replacement. The established first line treatment is surgical repair; however, this may not be feasible in all patients. Percutaneous treatment of ascending thoracic pseudoaneurysms has been described as an alternative for nonsurgical candidates. Utilization of multimodality imaging can prove invaluable in minimizing the risk of potentially fatal intra-procedural complications. We present a case of successful embolization using computer tomography-guided direct percutaneous puncture of the pseudoaneurysm, with concomitant endovascular treatment under fluoroscopic and intravascular ultrasound guidance in a patient with challenging vascular anatomy.

Pulse wave velocity involving proximal portions of the aorta correlates with the degree of aortic dilatation at the sinuses of valsalva in ascending thoracic aortic aneurysms.

OBJECTIVE: To determine the relationship between arterial stiffness measured in different aortic segments and the presence and extent of ascending thoracic aortic aneurysm (ATAA). METHODS: Patients at a Thoracic Aortic Diseases clinic at a University teaching hospital were compared to patients attending a Cardiology outpatient Clinic at the same institution. A non-invasive measure of vascular stiffness was performed using pulse wave velocity (PWV) measurement of several vascular segments-carotid-femoral pulse wave velocity (cfPWV), heart-femoral pulse wave velocity (hfPWV) and brachial-ankle pulse wave velocity (baPWV). Aortic dimensions were measured on echocardiogram. RESULTS: Patients with ATAA (N = 32) were 66 years and the same age as those without ATAA (N = 46). There was no significant difference between those with or without aortic aneurysm with respect to cfPWV, hfPWV or baPWV. In ATAA, there was a significant (p <0.05) inverse correlation between aortic diameter at the sinuses of Valsalva and cfPWV, as well as hfPWV, but not with baPWV. This relationship was not evident in persons without ATAA. CONCLUSION: Reduced aortic stiffness (increased compliance), assessed by cfPWV or hfPWV, correlates with larger aortic size of ATAA at the level of the sinuses of Valsalva but not at the ascending aorta, suggesting cfPWV may be a useful method to assess the size of ATAA at the level of the sinuses of Valsalva. Overall aortic stiffness assessed by PWV did not differentiate persons with or without an ATAA, in individuals who do not have a genetic or inheritable cause of their ATAA.

Long-term outcomes after thoracic aortic surgery: a population-based study.

OBJECTIVE: Long-term survival after aortic surgery has remained largely unexplored, despite suggestions of superior durability compared with endovascular techniques. The objective of the present study was to determine the long-term survival after open thoracic aortic surgery and to identify the predictors of mortality. METHODS: The provincial database was accessed to identify all adult patients who had undergone primary open thoracic aortic surgery in British Columbia since 1993. Kaplan-Meier survival analyses were performed for the entire group and by year of surgery, urgency of surgery, and aortic segment requiring surgery. Multivariate analyses were performed to identify the predictors of mortality. RESULTS: From January 1993 to June 2010, 1960 patients underwent primary open thoracic aortic surgery at 4 hospitals in British Columbia. Overall, the 30-day mortality was 9.1%, with a perioperative stroke rate of 5.8%. Long-term survival was 77.7%, 59.6%, and 44.7% at 5, 10, and 15 years, respectively. Subanalyses demonstrated improved long-term survival in the modern era; among patients undergoing elective aortic surgery; and among patients undergoing surgery on the ascending aorta or aortic root (P < .0001). The preoperative characteristics associated with decreased long-term survival included age older than 65 years, acute renal failure, dialysis, cerebrovascular accident, chronic obstructive pulmonary disease, peripheral vascular disease, and descending or thoracoabdominal aorta surgery. CONCLUSIONS: Long-term survival after elective thoracic aortic surgery is excellent, with improved outcomes in the modern era. Several preoperative risk factors associated with decreased survival were identified, which could assist in risk stratification and patient selection. Finally, the long-term survival rates identified in the present study should serve as a benchmark to which new aortic interventions should be compared.

Aortic wall stress in hypertension and ascending thoracic aortic aneurysms: implications for antihypertensive therapy.

The objective of this study was the evaluation of aortic wall stress in patients with ascending thoracic aortic aneurysms (TAA) because of the paucity of data to guide medical therapy for blood pressure (BP) management in TAA. Twelve men, age 67.4 ± 3.3 years (SEM) with hypertension and ascending TAA without other etiology, previous aortic surgery or associated significant aortic valve disease, had maximum dimensions of the ascending aorta measured from CT angiogram (CTa) and transthoracic echocardiogram (TTE) with aortic wall thickness measured on TTE. Wall stress (WS(σ)(P)) at peak systolic BP (SBP) was expressed by the equation: WS(σ)(P) = 2LCSA × SBP/MCSA, where LCSA is ascending aorta luminal cross-sectional area; MCSA is the surface area of the aortic wall cross sectional area considering aortic wall thickness. There was no significant difference in wall stress from TTE or CTa although mean wall stress was slightly larger when calculated from CTa. For each 5 mmHg increment in Systolic BP (SBP), there was a 3.9 kPa increase in wall stress that was 3.5 kPa for small aneurysms (40 to <45 mm) and 4.4 kPa for larger aneurysms (45-52 mm). There was a 33.0 ± 1.2 % reduction in wall stress when SBP went from 165 to 110 mmHg with a 21.0 ± 0.7 % reduction in wall stress found when SBP was reduced from 140 to 110 mmHg. These data, in patients with hypertension and ascending TAA suggest that meaningful reductions in aortic wall stress occur with reductions of SBP and this benefit extends to SBP levels <140 mmHg.

Vancouver simplified grading system with computed tomographic angiography for blunt aortic injury.

OBJECTIVE: Delineation of blunt aortic injury by computed tomographic angiography guides management of this potentially fatal injury. Two existing grading systems are problematic to apply and not linked to outcomes. A simplified computed tomographic angiography-based grading system, linked to clinical outcomes, was developed, and feasibility and reliability were evaluated. METHODS: Retrospective review was performed of all blunt aortic injury cases presenting to a single provincial quaternary referral center designated for blunt aortic injury management between 2001 and 2009. Management, associated injuries, hospital survival, and cause of death were determined. Initial computed tomographic angiography was reviewed, and injuries were graded according to the new Vancouver simplified grading system by 2 study authors. Three additional trauma radiologists then graded the aortic injuries with the 2 existing systems and the simplified system. Interrater reliability was determined. RESULTS: Forty-eight patients were identified. Two had minimal aortic injury (grade I), 7 had an intimal flap larger than 1 cm (grade II), 32 had traumatic pseudoaneurysm (grade III), 6 had active contrast extravasation (grade IV), and 1 could not be rated. Survivals were 100%, 90%, and 33% for grades I and II, III, and IV, respectively. Of grade III injuries, 14% were medically managed, 68% repaired endovascularly, and 18% repaired with open surgery. Interrater correlation was best with the simplified score, with only 0.5% of cases unable to be classified. CONCLUSIONS: The Vancouver simplified blunt aortic injury grading system is easy to use and correlates with clinical outcomes. Prospective external validation is required.

Prophylactic intravenous magnesium sulphate in addition to oral {beta}-blockade does not prevent atrial arrhythmias after coronary artery or valvular heart surgery: a randomized, controlled trial.

BACKGROUND: Atrial arrhythmias (AA) are an important cause of morbidity after cardiac surgery. Efforts at prevention of postoperative AA have been suboptimal. Perioperative beta-blocker administration is the standard of care at many centers. Although prophylactic administration of magnesium sulfate (MgSO(4)) has been recommended, review of all previously published trials of MgSO(4) reveals conflicting results. This study was designed to address methodological shortcomings from previous studies and is the largest randomized, placebo-controlled trial of intravenous (IV) MgSO(4) for the prevention of AA after coronary artery bypass grafting or cardiac valvular surgery. METHODS AND RESULTS: A total of 927 nonemergent cardiac surgery patients were stratified into 2 groups: isolated coronary artery bypass grafting (n=694), or valve surgery with or without coronary artery bypass grafting (n=233), and randomized to receive either 5g IV MgSO(4) or placebo on removal of the cross-clamp, followed by daily 4-hour infusions, from postoperative day 1 until postoperative day 4. All patients were treated according to an established oral beta-blocker protocol. Postoperative serum Mg levels were checked and standard of care was to administer IV MgSO(4) for low serum levels. The primary end point was AA lasting > or =30 minutes or requiring treatment for hemodynamic compromise. There were no differences in the incidence of AA between patients who received IV MgSO(4) or placebo (26.4% versus 24.3%, respectively). The results were similar when broken down according to stratified groups. CONCLUSIONS: In patients treated with a protocol for postoperative oral beta-blocker after nonemergent cardiac surgery, the addition of prophylactic IV MgSO(4) did not reduce the incidence of AA.

Seven-year results with the St Jude Medical Silzone mechanical prosthesis.

OBJECTIVE: The Artificial Valve Endocarditis Reduction Trial was stopped on January 21, 2000, due to a higher incidence of paraprosthetic leak in the St Jude Medical Silzone prosthesis compared with the conventional prosthesis. The Artificial Valve Endocarditis Reduction Trial investigators reported the 2-year results in 2002. This retrospective study assessed the influence on thromboembolism and paraprosthetic leak to 7 years. METHODS: A total of 253 patients had 254 operations: 80 aortic valve replacements, 139 mitral valve replacements, and 35 multiple replacements with placement of Silzone prostheses. The mean age was 58.6 years (range 21-84 years, median age 59.8 years), and there were 126 women (49.8%) and 74 concomitant procedures (coronary artery bypass 28.9%). RESULTS: Major paraprosthetic leak (repair, re-replacement, or mortality) occurred in 10 of the original procedures after 30 days (3 aortic valve replacements, 3 mitral valve replacements, 4 multiple replacements). Nine occurrences in 8 patients-5 early (2 years)-were managed. Seven were managed with definitive re-replacement. One was an early nonoperative fatality. There was 1 late fatality after the second late paraprosthetic leak reoperation. One of the 10 procedures occurring after 2 years had mild to moderate aortic valve replacement paraprosthetic leak managed as an incidental re-replacement at the time of correction of supra valvular patch stenosis. One additional occurrence, in addition to the 8 patients (<30 days), was considered a technical error and not related to the Silzone prosthesis and was replaced with a Silzone prosthesis. The linearized rate of paraprosthetic leak within the first 2 years of follow-up was 1.3%/patient-year and after 2 years was 0.4%/patient-year. The linearized occurrence rate for major thromboembolism was 0.42%/patient-year for aortic valve replacement and 1.71%/patient-year for mitral valve replacement. CONCLUSIONS: Paraprosthetic leak with the St Jude Medical Silzone prosthesis was managed both during the early (2years) intervals with re-replacement. Late managed events may be manifestations of earlier occurring paraprosthetic leak. Follow-up echocardiograms should meet standards of care, 6 to 12 months after surgery and at the slightest suspicion of dysfunction. There is no advanced continuing risk of the St Jude Medical Silzone prosthesis.

Mitral valve disease: if the mitral valve is not reparable/failed repair, is bioprosthesis suitable for replacement?

OBJECTIVE: The durability of mitral bioprostheses has long been known to be inferior to aortic bioprostheses. Mitral valve reconstruction/repair is currently recommended for most mitral valve procedures. The choice of prostheses for non-reparable or failed mitral valve repairs has not been specified or given appropriate attention within the literature. The objective of this study is to address the role of bioprostheses in the specific subset of non-reparable or failed repair patients by using the knowledge of the general durability of mitral porcine bioprostheses, inclusive of the Carpentier-Edwards mitral porcine bioprosthesis. METHODS: The CE-SAV was implanted in 1135 patients (1175 operations) for mitral valve replacement (MVR) from 1982 to 2000. The mean age was 65.0+/-12.1 years (range 13-86 years). The mean follow-up was 6.4+/-4.5 years, 7555.9 patient-years and 98.3% complete. The evaluation considered freedom from structural valve deterioration (SVD) and freedom from composites of complications, as well as risk assessment. RESULTS: For the 51-60 year age group, the actual and actuarial freedom from SVD was, at 18 years, 56.0+/-4.1% and 14.7+/-5.8%; for the 61-70 year age group was, at 18 years, 69.6+/-2.6% and 26.5+/-5.9%, respectively. For the >70 group, at 15 years was 92.2+/-2.0% and 69.0+/-9.7%, respectively. There were a total of 256 SVD events with 31 fatalities and 226 reoperations with 10 fatalities (4.42%). The predictors of SVD were age (hazard ratio [HR] 0.98, p=0.0002), concomitant CAB (HR 0.66, p=0.020) and valve size (HR 1.08, p=0.034). The overall actual freedom, at 15-18 years, for >70 age group was, for valve-related reoperation, 94.3+/-1.5%; and for valve-related mortality was 87.8+/-2.3%. CONCLUSIONS: The CE-SAV mitral porcine bioprosthesis cannot be recommended as representative of prosthesis-type of choice for non-reparable or failed repair of native mitral valves for ages 70 years of age. The clinical performance of the CE-SAV is similar to other mitral bioprostheses.

P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis.

BACKGROUND: Evaluate the potential role of p38 inhibitors for the treatment of osteoarthritis using an animal model of joint degeneration (iodoacetate-induced arthritis) and a pain model (Hargraeves assay). METHODS: P38 kinase activity was evaluated in a kinase assay by measuring the amount of phosphorylated substrate ATF2 using a phosphoATF2 (Thr71) specific primary antibody and an alkaline phosphate coupled secondary antibody and measuring the OD at 405 nm. TNFalpha and IL-1beta secretion from LPS stimulated THP-1 monocytic cells and human peripheral blood mononuclear cells were measured by ELISA. Rats treated with vehicle or p38 inhibitor were injected intra-articularly in one knee with iodoacetate and damage to the tibial plateau was assessed from digitized images captured using an image analyzer. The effect of p38 inhibitors on hyperalgesia was evaluated in rats given an intraplantar injection of carrageenan and 4 h later the paw withdrawal time to a radiant heat source was measured. RESULTS: SB-203580 and VX-745 are both potent inhibitors of p38 with IC50s of 136 +/- 64 nM and 35 +/- 14 nM (mean +/- S.D.), respectively. Similarly, SB-203580 and VX-745 potently inhibited TNF release from LPS stimulated human THP-1 cells with IC50s of 72 +/- 15 nM; and 29 +/- 14 nM (mean +/- S.D.) respectively. TNF release from LPS stimulated human peripheral blood mononuclear cells was inhibited with IC50s 16 +/- 6 nM and 14 +/- 8 nM, (mean +/- S.D.) for SB-203580 and VX-745 and IL-1 was inhibited with IC50s of 20 +/- 8 nM and 15 +/- 4 nM (mean +/- S.D.), respectively. SB-203580 and VX-745 administered orally at a dose of 50 mg/kg resulted in the significant (p < 0.05) inhibition of joint degeneration in the rat iodoacetate model of 45% and 31%, respectively. SB-203580 demonstrated a dose related inhibition of joint degeneration of 30, 25, 12 and 8% at 50, 25, 10 and 5 mg/kg p.o. b.i.d. in the rat iodoacetate model. Similarly, both p38 inhibitors significantly (p < 0.05) attenuated the pain response (paw withdrawal time) in the Hargraeves hyperalgesia assay when administered orally at 30, 10 and 3 mg/kg. CONCLUSION: SB203580 and VX-745 demonstrated attenuation of both cartilage degeneration and pain in animal models and suggest that p38 inhibitors may be a useful approach for the treatment of osteoarthritis.

Early antithrombotic therapy for aortic valve bioprostheses: is there an indication for routine use?

BACKGROUND: Consensus reports over the past 10 years from the United States, Europe, United Kingdom, and Canada have not provided consistent guidelines for antithrombotic therapy of aortic valve bioprostheses for the three-month period after surgery. This study was conducted to determine if antithrombotic therapy was protective against TE with aortic bioprostheses 30 days or less after aortic valve replacement (AVR). METHODS: From 1994 to 2000, 1,372 patients implanted with three currently marketed aortic bioprostheses, Medtronic Mosaic (Medtronic, Inc, Minneapolis, MN) (415 patients), Carpentier-Edwards SAV (462), and Carpentier-Edwards PERIMOUNT (495) (Edwards Lifesciences, Irvine, CA), with a mean age of greater than 70 years were evaluated. Patient populations were comparable, inclusive of concomitant coronary artery bypass grafting (CABG) for the overall populations and for patients greater than 70 years. RESULTS: There were 37 thromboembolic (TE) events: major TE, 14; reversible ischemic neurologic deficit (RIND), 12; and minor TE, 11. There were 4 TE deaths. Multivariate (stepwise logistic regression) analysis revealed no predictive risk factors for overall TE. For the combination of major TE plus RIND there were two predictive risk factors with analysis of 12 risk variables: preoperative cerebrovascular accident (odds ratio [OR] 4.45, 95% confidence interval [CI] 1.17 to 16.87, p = 0.028); and concomitant CABG (OR 3.19, 95% CI 1.16 to 8.76, p = 0.025). Neither anticoagulant nor antiplatelet therapies gave significant protection. CONCLUSIONS: There does not appear to be an indication for routine antithrombotic management. The study supports the potential use of antithrombotic therapy for comorbidities of preoperative cerebrovascular accident and concomitant CABG but not atrial fibrillation, left ventricular dysfunction, or elderly age greater than 70 years. Vascular burden and advanced age are likely contributing factors to these independent predictors. There may still be a need for, or at least consideration of, a randomized trial for AVR with bioprostheses.

The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck).

This communication details the synthesis, biological activity, and binding mode of a novel class of 2-benzimidazole substituted pyrimidines. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase and a representative analog was co-crystallized with Hck (a structurally related member of the Src family kinases).

The development of novel 1,2-dihydro-pyrimido[4,5-c]pyridazine based inhibitors of lymphocyte specific kinase (Lck).

This communication details the synthesis, biological activity, and proposed binding mode of a novel class of tri-cyclic derivatives of 1,2-dihydro-pyrimido[4,5-c]pyridazines 1 and 2. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase.

The development of novel C-2, C-8, and N-9 trisubstituted purines as inhibitors of TNF-alpha production.

A series of C-2, C-8, and N-9 trisubstituted purine based inhibitors of TNF-alpha production are described. The most potent analogs showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell based assay. The SAR of the series was optimized with the aid of X-ray co-crystal structures of these inhibitors bound with mutated p38 (mp38).

Development of N-4,6-pyrimidine-N-alkyl-N'-phenyl ureas as orally active inhibitors of lymphocyte specific tyrosine kinase.

A new class of lymphocyte specific tyrosine kinase (lck) inhibitors based on an N-4,6-pyrimidine-N-alkyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar inhibition of lck kinase activity as well as IL-2 synthesis from Jurkat cells. One of these analogs, 7i, was shown to be orally efficacious by in vivo testing in a rat adjuvant-induced arthritis study.

Development of N-2,4-pyrimidine-N-phenyl-N'-alkyl ureas as orally active inhibitors of tumor necrosis factor alpha (TNF-alpha) synthesis. Part 2.

A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N'-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.