SAR of 4-Hydroxypiperidine and Hydroxyalkyl Substituted Heterocycles as Novel p38 Map Kinase Inhibitors Laszlo Revesz, a, * Franco E. Di Padova, a Thomas Buhl, a Roland Feifel, a Hermann Gram, a Peter Hiestand, a Ute Manning a and Alfred G. Zimmerlin b a Arthritis and Bone Research, Novartis Pharma AG, CH-4002 Switzerland b Preclinical Safety, Novartis Pharma AG, CH-4002 Switzerland Received 14 February 2000; accepted 30 March 2000 AbstractÐThe 4-hydroxypiperidine substituent was found to confer high p38 selectivity devoid of COX-1 anity, when attached to a series of pyridinyl substituted heterocycles. Pyridinyloxazole 11 showed a promising in vivo pro®le with bioavailability of 64% and ED 50 in rat collagen induced arthritis of 10 mg/kg po bid. In contrast to pyridinylimidazoles such as SB 203580, 11 did not inhibit human cytochrome P450 isoenzymes. # 2000 Elsevier Science Ltd. All rights reserved. Introduction Inhibitors of p38 MAP kinase reduce the production of pro-in¯ammatory cytokines, e.g., IL-1, TNF-a, IFN-g and IL-6, whose excessive production initiates events leading to in¯ammation and tissue destruction in dis- eases such as rheumatoid arthritis (RA). 1 p38 inhibitors not only block the synthesis but also the signal cascades induced by these cytokines; 2 in addition, p38 has been implicated in the induction of COX-2, the inducible pros- taglandin cyclooxygenase. 3 The interest in the development of p38 MAP kinase inhibitors is based on the expecta- tions, that p38 inhibiting drugs will treat the underlying cause of chronic in¯ammatory diseases and stop their progression. The present report describes eorts in the search, design and synthesis of p38 inhibitors and gives some results on biological activities. Results and Discussion Pyridinylimidazole SB 203580 is one of the best studied p38 inhibitors reported to date, with oral activity in several animal models of chronic in¯ammatory disease. 4 Pre- sumably, modest bioavailability, toxicity and cytochrome P450 inhibition precluded its further development. As a predecessor of SB 203580, we claimed 1 5 in 1972 as an anti-in¯ammatory agent, long before its target p38 was identi®ed. Compound 1 is a moderately potent p38a inhibitor (IC 50 =0.45 mM), but shows COX-1 inhibition (IC 50 =5 mM) representing an unacceptable ulceration risk. Since pyridinylimidazoles including SB 203580 6 often block both enzymes, the design and synthesis of selective p38 inhibitors devoid of COX-1 inhibition became our primary goal. COX-1 activity appeared to be related to the lipophilicity of the substituent in position 2 of the imidazole ring. Replacement of one C-atom of the tert butyl group in 1 by a polar hydroxy functionality led to the selective p38 inhibitors 2 and 3 (Table 1). By increasing ring size and lipophilicity of the hydroxycycloalkyl group to 4-, 5-, 6-, or 7-membered rings, COX-1 inhibition gradually returned. Although 3 in Table 1 showed the best p38a/COX-1 selectivity ratio, 6 was preferred for further optimisation 0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(00)00200-6 Bioorganic & Medicinal Chemistry Letters 10 (2000) 1261±1264 *Corresponding author. Tel.: +41-61-324-3231; fax: +41-61-324- 2379; e-mail: laszlo.revesz@pharma.novartis.com