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This paper describes the development of the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 from a lead series of 4-anilinoquinazoline compounds. ZD1839 has suitable properties for use as a clinically effective drug and shows activity against human tumours. In particular, the use of pharmacokinetic data in the development of ZD1839 is… (More)
Smell impairment affects 1-2% of Americans and leads to frequent physician visits. Olfactory functional testing is available in chemosensory centers, but is frequently omitted in routine cranial nerve examinations. A new smell test, using the standard 70% isopropyl alcohol pad, was developed at the UCSD Nasal Dysfunction Clinic: The Alcohol Sniff Test… (More)
The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo… (More)
The authors have investigated the thesis that intermittent hearing impairment due to middle ear disease in the early years of life results in a central auditory disturbance which may persist in adulthood. The concept that, during the speech development years, auditory disturbances interfere with the normal maturation of central auditory processing appear to… (More)
Hearing loss, whether peripheral or central, compounds the communication and educational problems of the learning disabled student. A central auditory processing disorder uniquely interferes with both the input and integration of verbal information, further resulting in a potentially permanent cognitive dysfunction during the developmental period of… (More)
A high-throughput screen targeting the EP(1) receptor identified non-acidic glycine sulfonamide derivative 2a with a pK(i) of 6.2. Analogue synthesis allowed a thorough investigation of the structure-activity relationship (SAR) and led to a 100-fold increase in recombinant potency.
The phenomenon of central presbycusis has been investigated employing a central auditory battery in elderly individuals with essentially normal hearing. The studies indicate a progressive loss in central auditory competence measured by simultaneous binaural challenges and frequency and temporal distortion tests. The rate of failure is related to age, on the… (More)
A group of dyslexic pupils with normal end organ function was studied by a central auditory battery to determine whether a hearing disability existed. The clinical features of dyslexia are presented with emphasis on the psychological developmental and functional disorders associated with this reading problem. The central battery of Willeford was selected as… (More)
A novel series of oxadiazole EP1 receptor antagonists was identified by replacing the amide of a known glycine sulfonamide derivative with a 1,3,4-oxadiazole. Optimization of the substitution patterns on the three aromatic rings led to the identification of high affinity EP1 receptor antagonists. The derivative with highest affinity displayed a binding IC50… (More)
Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.